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Contextual and spatial systems facilitate changes in emotional memory regulation brought on by traumatic stress. Cholinergic basal forebrain (chBF) neurons provide input to contextual/spatial systems and although chBF neurons are important for emotional memory, it is unknown how they contribute to the traumatic stress effects on emotional memory. Clusters of chBF neurons that project to the prefrontal cortex (PFC) modulate fear conditioned suppression and passive avoidance, while clusters of chBF neurons that project to the hippocampus (Hipp) and PFC (i.e. cholinergic medial septum and diagonal bands of Broca (chMS/DBB neurons) are critical for fear extinction. Interestingly, neither Hipp nor PFC projecting chMS/DBB neurons are critical for fear extinction. The retrosplenial cortex (RSC) is a contextual/spatial memory system that receives input from chMS/DBB neurons, but whether this chMS/DBB-RSC circuit facilitates traumatic stress effects on emotional memory remain unexplored. Traumatic stress leads to neuroinflammation and the buildup of reactive oxygen species. These two molecular processes may converge to disrupt chBF circuits enhancing the impact of traumatic stress on emotional memory. • chBF systems project to contextual/spatial systems. • Contextual/spatial systems are sensitive to traumatic stress. • chBF systems are critical for emotional memory regulation. • chBF systems may be sensitive to traumatic stress. • Traumatic stress may disrupt emotional memory regulation via chBF systems. [ABSTRACT FROM AUTHOR]

Deficits in hippocampus‐dependent memory processes are common across psychiatric and neurodegenerative disorders such as depression, anxiety and Alzheimer's disease. Moreover, stress is a major environmental risk factor for these pathologies and it exerts detrimental effects on hippocampal functioning via the activation of hypothalamic–pituitary–adrenal (HPA) axis. The medial septum cholinergic neurons extensively innervate the hippocampus. Although, the cholinergic septohippocampal pathway (SHP) has long been implicated in learning and memory, its involvement in mediating the adaptive and maladaptive impact of stress on mnemonic processes remains less clear. Here, we discuss current research highlighting the contributions of cholinergic SHP in modulating memory encoding, consolidation and retrieval. Then, we present evidence supporting the view that neurobiological interactions between HPA axis stress response and cholinergic signalling impact hippocampal computations. Finally, we critically discuss potential challenges and opportunities to target cholinergic SHP as a therapeutic strategy to improve cognitive impairments in stress‐related disorders. We argue that such efforts should consider recent conceptualisations on the dynamic nature of cholinergic signalling in modulating distinct subcomponents of memory and its interactions with cellular substrates that regulate the adaptive stress response. [ABSTRACT FROM AUTHOR]

Basal forebrain (BF) cholinergic neurons innervating the cortex regulate cognitive, specifically attentional, processes. Cholinergic atrophy and cognitive decline occur at an accelerated pace in age-related neurodegenerative disorders such as Alzheimer’s disease; however, the mechanism responsible for this phenomenon remains unknown. Here we hypothesized that developmental suppression of nerve growth factor signaling, mediated via tropomyosin-related kinase A (trkA) receptors, would escalate age-related attentional vulnerability. An adeno-associated viral vector expressing trkA shRNA (AAV-trkA) was utilized to knockdown trkA receptors in postnatal rats at an ontogenetic time point when cortical cholinergic inputs mature, and the impact of this manipulation on performance was assessed in animals maintained on an operant attention task throughout adulthood and until old (24 months) age. A within-subject comparison across different time points illustrated a gradual age-related decline in attentional capacities. However, the performance under baseline and distracted conditions did not differ between the AAV-trkA-infused and animals infused with a vector expressing shRNA against the control protein luciferase at any time point. Additional analysis of cholinergic measures conducted at 24 months showed that the capacity of cholinergic terminals to release acetylcholine following a depolarizing stimulus, cortical cholinergic fiber density and BF cholinergic cell size remained comparable between the two groups. Contrary to our predictions, these data indicate that developmental BF trkA disruption does not impact age-related changes in attentional functions. It is possible that life-long engagement in cognitive activity might have potentially rescued the developmental insults on the cholinergic system, thus preserving attentional capacities in advanced age. [ABSTRACT FROM AUTHOR]

Rationale: Cognitive flexibility is a key component of executive function and is disrupted in major psychiatric disorders. Brain-derived neurotrophic factor (BDNF) exerts neuromodulatory effects on synaptic transmission and cognitive/affective behaviors. However, the causal mechanisms linking BDNF hypofunction with executive deficits are not well understood. Objectives: Here, we assessed the consequences of BDNF hemizygosity on cognitive flexibility in mice performing an operant conditioning task. As dopaminergic-glutamatergic interaction in the striatum is important for cognitive processing, and BDNF heterozygous (BDNF) mice display a higher dopamine tone in the dorsal striatum, we also assessed the effects of partial striatal dopamine depletion on task performance and glutamate release. Results: BDNF mice acquired discrimination learning as well as new rule learning during set-shifting as efficiently as wild-type mice. However, partial removal of striatal dopaminergic inputs with 6-hydroxydopamine (6-OHDA) impaired these cognitive processes by impeding the maintenance of a new learning strategy in both genotypes. BDNF mutants exhibited performance impairments during reversal learning, and these deficits were associated with increased perseveration to the previously acquired strategy. Partial dopamine depletion of the striatum reversed these cognitive impairments. Additionally, reduction in depolarization-evoked glutamate release noted in the dorsal striatum of BDNF mice was not observed in 6-OHDA-infused BDNF mutants indicating normalization of glutamatergic transmission in these animals. Conclusions: Our data illustrate that BDNF signaling regulates cognitive control processes presumably by maintaining striatal dopamine-glutamate balance. Moreover, aberrations in BDNF signaling may act as a common neurobiological substrate that accounts for executive dysfunction observed in multiple psychiatric conditions. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of tobacco use in the population with schizophrenia is enormously high. Moreover, nicotine dependence is found to be associated with symptom severity and poor outcome in patients with schizophrenia. The neurobiological mechanisms that explain schizophrenia-nicotine dependence comorbidity are not known. This study systematically reviews the evidence highlighting the contribution of nicotinic acetylcholine receptors (nAChRs) to nicotine abuse in schizophrenia.Methods: Electronic data bases (Medline, Google Scholar, and Web of Science) were searched using the selected key words that match the aims set forth for this review. A total of 276 articles were used for the qualitative synthesis of this review.Results: Substantial evidence from preclinical and clinical studies indicated that dysregulation of α7 and β2-subunit containing nAChRs account for the cognitive and affective symptoms of schizophrenia and nicotine use may represent a strategy to remediate these symptoms. Additionally, recent meta-analyses proposed that early tobacco use may itself increase the risk of developing schizophrenia. Genetic studies demonstrating that nAChR dysfunction that may act as a shared vulnerability factor for comorbid tobacco dependence and schizophrenia were found to support this view. The development of nAChR modulators was considered an effective therapeutic strategy to ameliorate psychiatric symptoms and to promote smoking cessation in schizophrenia patients.Conclusions: The relationship between schizophrenia and smoking is complex. While the debate for the self-medication versus addiction vulnerability hypothesis continues, it is widely accepted that a dysfunction in the central nAChRs represent a common substrate for various symptoms of schizophrenia and comorbid nicotine dependence. [ABSTRACT FROM AUTHOR]

Nicotine is a major psychoactive and addictive component of tobacco. Although cessation of tobacco use produces various somatic and affective symptoms, withdrawal-related cognitive deficits are considered to be a critical symptom that predict relapse. Therefore, delineating the cognitive mechanisms of nicotine withdrawal may likely provide gainful insights into the neurobiology of nicotine addiction. The present study was designed to examine the effects of nicotine withdrawal induced by mecamylamine, a non-specific nicotinic receptor (nAChR) antagonist, on cognitive control processes in mice using an operant strategy switching task. Brain-derived neurotrophic factor (BDNF) modulates synaptic transmission in frontostriatal circuits, and these circuits are critical for executive functions. Thus, we examined the effects of mecamylamine-precipitated nicotine withdrawal on prefrontal and striatal BDNF protein expression. Mice undergoing precipitated nicotine withdrawal required more trials to attain strategy switching criterion as compared to the controls. Error analysis indicated that impaired performance in these animals was mostly related to their inability to execute the new strategy. The striatal/prefrontal BDNF ratios robustly increased following precipitated nicotine withdrawal. Moreover, higher BDNF ratios were associated with longer task acquisition. Collectively, our findings illustrate that mecamylamine-induced nicotine withdrawal disrupts cognitive control processes and that these changes are possibly linked to perturbations in frontostriatal BDNF signaling. [ABSTRACT FROM AUTHOR]

Substantial evidence suggests that cerebral deposition of the neurotoxic fibrillar form of amyloid precursor protein, β-amyloid (Aβ), plays a critical role in the pathogenesis of Alzheimer's disease (AD). Yet, many aspects of AD pathology including the cognitive symptoms and selective vulnerability of cortically projecting basal forebrain (BF) cholinergic neurons are not well explained by this hypothesis. Specifically, it is not clear why cognitive decline appears early when the loss of BF cholinergic neurons and plaque deposition are manifested late in AD. Soluble oligomeric forms of Aβ are proposed to appear early in the pathology and to be better predictors of synaptic loss and cognitive deficits. The present study was designed to examine the impact of Aβ oligomers on attentional functions and presynaptic cholinergic transmission in young and aged rats. Chronic intracranial infusions of Aβ oligomers produced subtle decrements in the ability of rats to sustain attentional performance with time on task, irrespective of the age of the animals. However, Aβ oligomers produced robust detrimental effects on performance under conditions of enhanced attentional load in aged animals. In vivo electrochemical recordings show reduced depolarization-evoked cholinergic signals in Aβ-infused aged rats. Moreover, soluble Aβ disrupted the capacity of cholinergic synapses to clear exogenous choline from the extracellular space in both young and aged rats, reflecting impairments in the choline transport process that is critical for acetylcholine (ACh) synthesis and release. Although aging per se reduced the cross-sectional area of BF cholinergic neurons and presynaptic cholinergic proteins in the cortex, attentional performance and ACh release remained unaffected in aged rats infused with the control peptide. Taken together, these data suggest that soluble Aβ may marginally influence attentional functions at young ages primarily by interfering with the choline uptake processes. However, age-related weakening of the cholinergic system may synergistically interact with these disruptive presynaptic mechanisms to make this neurotransmitter system vulnerable to the toxic effects of oligomeric Aβ in robustly impeding attentional capacities. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that diminished ability to control cocaine seeking arises from perturbations in glutamate homeostasis in the nucleus accumbens. However, the neurochemical substrates underlying cocaine-induced neuroadaptations in the dorsal striatum and how these mechanisms link to behavioral plasticity is not clear. We employed glutamate-sensitive microelectrodes and amperometry to study the impact of repeated cocaine administration on glutamate dynamics in the dorsolateral striatum of awake freely-moving rats. Depolarization-evoked glutamate release was robustly increased in cocaine-pretreated rats challenged with cocaine. Moreover, the clearance of glutamate signals elicited either by terminal depolarization or blockade of non-neuronal glutamate transporters slowed down dramatically in cocaine-sensitized rats. Repeated cocaine exposure also reduced the neuronal tone of striatal glutamate. Ceftriaxone, a β-lactam antibiotic that activates the astrocytic glutamate transporter, attenuated the effects of repeated cocaine exposure on synaptic glutamate release and glutamate clearance kinetics. Finally, the antagonism of AMPA glutamate receptors in the dorsolateral striatum blocked the development of behavioral sensitization to repeated cocaine administration. Collectively, these data suggest that repeated cocaine exposure disrupts presynaptic glutamate transmission and transporter-mediated clearance mechanisms in the dorsal striatum. Moreover, such alterations produce an over activation of AMPA receptors in this brain region leading to the sensitized behavioral response to repeated cocaine. [ABSTRACT FROM AUTHOR]

Functional variation in the gene encoding the presynaptic choline transporter (CHT) has been linked to attention-deficit/hyperactivity disorder. Here, we report that a heterozygous deletion in the CHT gene in mice (CHT-/- ) limits the capacity of cholinergic neurons to sustain acetylcholine (ACh) release and attentional performance. Cortical microdialysis and amperometric methods revealed that, whereas wild-type and CHT+/- ' animals support equivalent basal ACh release and choline clearance, CHT+/- animals exhibit a signif-icant inability to elevate extracellular ACh following basal forebrain stimulation, in parallel with a diminished choline clearance capacity following cessation of stimulation. Consistent with these findings, the density of CHTs in cortical synaptosomal plasma membrane-enriched fractions from unstimulated CHT+/- animals matched those observed in wild-type animals despite reductions in CHT levels in total extracts, achieved via a redistribution of CHT from vesicle pools. As a consequence, in CHT+/- animals, basal forebrain stimulation was unable to mobilize wild-type quantities of CHT to the plasma membrane. In behavioral studies, CHT+/- mice were impaired in performing a sustained attention task known to depend on cortical cholinergic activity. In wild-type mice, but not CHT+/- mice, attentional performance increased the density of CHTs in the synaptosomal membrane in the right frontal cortex. Basal CHT levels in vesicle-enriched membranes predicted the degree of CHT mobilization as well as individual variations in performance on the sustained attention task. Our findings demonstrate biochemical and physiological alterations that underlie cognitive impairments associated with genetically imposed reductions in choline uptake capacity. [ABSTRACT FROM AUTHOR]

The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno-associated viral vector-based RNA interference ( AAV- RNAi) strategy to suppress the expression of tropomyosin-related kinase A (trk A) receptors by cholinergic neurons in the nucleus basalis of Meynert/substantia innominata ( nMB/ SI) of adult and aged rats. Suppression of trk A receptor expression impaired attentional performance selectively in aged rats. Performance correlated with trk A levels in the nMB/ SI. trk A knockdown neither affected nMB/ SI cholinergic cell counts nor the decrease in cholinergic cell size observed in aged rats. However, trk A suppression augmented an age-related decrease in the density of cortical cholinergic processes and attenuated the capacity of cholinergic neurons to release acetylcholine ( ACh). The capacity of cortical synapses to release ACh in vivo was also lower in aged/trk A- AAV-infused rats than in aged or young controls, and it correlated with their attentional performance. Furthermore, age-related increases in cortical pro NGF and p75 receptor levels interacted with the vector-induced loss of trk A receptors to shift NGF signaling toward p75-mediated suppression of the cholinergic phenotype, thereby attenuating cholinergic function and impairing attentional performance. These effects model the abnormal trophic regulation of cholinergic neurons and cognitive impairments in patients with early Alzheimer's disease. This rat model is useful for identifying the mechanisms rendering aging cholinergic neurons vulnerable as well as for studying the neuropathological mechanisms that are triggered by disrupted trophic signaling. [ABSTRACT FROM AUTHOR]

Abstract: The use of an industry waste, brown coal fly ash collected from the Latrobe Valley, Victoria, Australia, has been tested for the post-combustion CO2 capture through indirect minersalization in acetic acid leachate. Upon the initial leaching, the majority of calcium and magnesium in fly ash were dissolved into solution, the carbonation potential of which was investigated subsequently through the use of a continuously stirred high-pressure autoclave reactor and the characterization of carbonation precipitates by various facilities. A large CO2 capture capacity of fly ash under mild conditions has been confirmed. The CO2 was fixed in both carbonate precipitates and water-soluble bicarbonate, and the conversion between these two species was achievable at approximately 60°C and a CO2 partial pressure above 3bar. The kinetic analysis confirmed a fast reaction rate for the carbonation of the brown coal ash-derived leachate at a global activation energy of 12.7kJ/mol. It is much lower than that for natural minerals and is also very close to the potassium carbonate/piperazine system. The CO2 capture capacity of this system has also proven to reach maximum 264kg CO2/tonne fly ash which is comparable to the natural minerals tested in the literature. As the fly ash is a valueless waste and requires no comminution prior to use, the technology developed here is highly efficient and energy-saving, the resulting carbonate products of which are invaluable for the use as additive to cement and in the paper and pulp industry. [Copyright &y& Elsevier]

One-second-long increases in prefrontal cholinergic activity ("transients") were demonstrated previously to be necessary for the incorporation of cues into ongoing cognitive processes ("cue detection"). Nicotine and, more robustly, selective agonists at α4β2* nicotinic acetylcholine receptors (nAChRs) enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of β2-containing and α7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the α4β2* nAChR agonist ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy) pyridine dihydrochloride], or theα7nAChR agonist A-582941 [2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole]. Transients were recorded in mice lacking β2 or α7 nAChRs and in rats after removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of α4β2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking β2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by β2* knock-out. Conversely, in mice lacking theα7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of α7 nAChR in controlling the duration of release events, stimulation of α7 nAChR produced cholinergic transients that lasted 10- to 15-fold longer than those evoked by nicotine. α7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal α4β2* nAChRs play a key role in evoking and facilitating the transient glutamatergic- cholinergic interactions that are necessary for cue detection and attentional performance. [ABSTRACT FROM AUTHOR]

Abstract: The identification and characterization of drugs for the treatment of cognitive disorders has been hampered by the absence of comprehensive hypotheses. Such hypotheses consist of (a) a precisely defined cognitive operation that fundamentally underlies a range of cognitive abilities and capacities and, if impaired, contributes to the manifestation of diverse cognitive symptoms; (b) defined neuronal mechanisms proposed to mediate the cognitive operation of interest; (c) evidence indicating that the putative cognition enhancer facilitates these neuronal mechanisms; (d) and evidence indicating that the cognition enhancer facilitates cognitive performance by modulating these underlying neuronal mechanisms. The evidence on the neuronal and attentional effects of nAChR agonists, specifically agonists selective for α4β2* nAChRs, has begun to support such a hypothesis. nAChR agonists facilitate the detection of signals by augmenting the transient increases in prefrontal cholinergic activity that are necessary for a signal to gain control over behavior in attentional contexts. The prefrontal microcircuitry mediating these effects include α4β2* nAChRs situated on the terminals of thalamic inputs and the glutamatergic stimulation of cholinergic terminals via ionotropic glutamate receptors. Collectively, this evidence forms the basis for hypothesis-guided development and characterization of cognition enhancers. [Copyright &y& Elsevier]

Traditional descriptions of the cortical cholinergic input system focused on the diffuse organization of cholinergic projections and the hypothesis that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. The ability of ACh to reach the extrasynaptic space (volume neurotransmission), as opposed to remaining confined to the synaptic cleft (wired neurotransmission), has been considered an integral component of this conceptualization. Recent studies demonstrated that phasic release of ACh, at the scale of seconds, mediates precisely defined cognitive operations. This characteristic of cholinergic neurotransmission is proposed to be of primary importance for understanding cholinergic function and developing treatments for cognitive disorders that result from abnormal cholinergic neurotransmission. [ABSTRACT FROM AUTHOR]

Abstract: Previous experiments demonstrated that second-based transient increases in choline concentrations measured by electrodes coated with choline oxidase (ChOx) and the amperometric detection of hydrogen peroxide validly indicate the depolarization-dependent release of acetylcholine (ACh) and its hydrolysis by endogenous acetylcholinesterase (AChE). Therefore, choline-sensitive microelectrodes have become valuable tools in neuropharmacological and behavioral research. The present experiments were designed to test the possibility that co-immobilization of ChOx plus AChE on recording sites increases the level of detection for evoked ACh release in the brain. If newly released ACh is not completely hydrolyzed by endogenous AChE and capable of reaching the extracellular space, currents recorded via sites equipped with both enzymes should be greater when compared with sites coated with ChOx only. Pairs of platinum-recording sites were coated either with AChE plus ChOx or ChOx alone. Potassium or nicotine-evoked currents were recorded throughout the entire dorsal–ventral extent of the medial prefrontal cortex (mPFC). The amplitudes of evoked cholinergic signals did not differ significantly between AChE+ChOx and ChOx-only coated recording sites. Additional experiments controlling for several potential confounds suggested that, in vivo, ACh levels ≥150fmol were detected by recordings sites featuring dual enzyme coating. Collectively, these results indicate that co-coating of microelectrodes with AChE does not enhance the detection of cholinergic activity in the cortex compared with measurements via recording sites coated only with ChOx. [Copyright &y& Elsevier]

Contrary to the classic description of acetylcholine (ACh) as a slowly acting neuromodulator that influences arousal states, results from experiments that employed enzyme-selective microelectrodes for the real-time monitoring of ACh release in the cortex of attentional task-performing rats indicate that cholinergic signals manifesting on multiple timescales (seconds, tens of seconds, and minutes) support, and are necessary for, the mediation of defined cognitive operations. Specifically, in the prefrontal cortex, second-based cholinergic signals support the detection of behaviorally significant cues. In contrast to these prefrontal cholinergic transients, performance-associated cholinergic activity that manifested at lower temporal resolution also was observed elsewhere in the cortex. Although tonic cholinergic signal levels were correlated with the amplitudes of cue-evoked cholinergic transients, and the latter with response latencies, the interrelationships and interactions between the multiple cholinergic signaling modes remains unclear. Hypotheses concerning the afferent circuitry contributing to the regulation of second- versus minute-based cholinergic signals are discussed. The discovery of cholinergic transients and their crucial role in cue detection and attentional performance form the basis for new hypotheses about the nature of cholinergic dysfunction in cognitive disorders and offer new targets for the development of treatments for the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Because modulation of cortical cholinergic neurotransmission has been hypothesized to represent a necessary mechanism mediating the beneficial cognitive effects of nicotine and nicotinic acetylcholine receptor (nAChR) subtype-selective agonists, we used choline-sensitive microelectrodes for the real-time measurement of ACh release in vivo, to characterize cholinergic transients evoked by nicotine and the α4β2*-selective nAChR partial agonist 2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride (ABT-089), a clinically effective cognition enhancer. In terms of cholinergic signal amplitudes, ABT-089 was significantly more potent than nicotine in evoking ACh cholinergic transients. Moreover, cholinergic signals evoked by ABT-089 were characterized by faster signal rise time and decay rate. The nAChRantagonist mecamylamine attenuated the cholinergic signals evoked by either compound. Cholinergic signals evoked by ABT-089 were more efficaciously attenuated by the relatively β2*-selective nAChR antagonist dihydro-β-erythroidine. The α7 antagonist methyllycaconitine did not affect choline signal amplitudes but partly attenuated the relatively slow decay rate of nicotine-evoked cholinergic signals. Furthermore, the AMPA receptor antagonist DNQX as well as the NMDA receptor antagonist APV more potently attenuated cholinergic signals evoked by ABT-089. Using glutamate-sensitive microelectrodes to measure glutamatergic transients, ABT-089 was more potent than nicotine in evoking glutamate release. Glutamatergic signals were highly sensitive to tetrodotoxin-induced blockade of voltage-regulated sodium channels. Together, the present evidence indicates that compared with nicotine, ABT-089 evokes more potent and sharper cholinergic transients in prefrontal cortex. Glutamatergic mechanisms necessarily mediate the cholinergic effects of nAChR agonists in the prefrontal cortex. [ABSTRACT FROM AUTHOR]

Summary: Cholinergic neurons originating from the basal forebrain innervate the entire cortical mantle. Choline-sensitive microelectrodes were used to measure the synaptic release of cortical acetylcholine (ACh) at a subsecond resolution in rats performing a task involving the detection of cues. Cues that were detected, defined behaviorally, evoked transient increases in cholinergic activity (at the scale of seconds) in the medial prefrontal cortex (mPFC), but not in a nonassociational control region (motor cortex). In trials involving missed cues, cholinergic transients were not observed. Cholinergic deafferentation of the mPFC, but not motor cortex, impaired cue detection. Furthermore, decreases and increases in precue cholinergic activity predicted subsequent cue detection or misses, respectively. Finally, cue-evoked cholinergic transients were superimposed over slower (at the timescale of minutes) changes in cholinergic activity. Cortical cholinergic neurotransmission is regulated on multiple timescales to mediate the detection of behaviorally significant cues and to support cognitive performance. [Copyright &y& Elsevier]

Abstract: Short-term (<45 days) treatment studies in rats have reported increased oxidative stress and oxidative (i.e., oxygen free radical-mediated) neural cell injury with typical antipsychotics such as haloperidol, but not with the atypicals such as clozapine, olanzapine or risperidone. However, now these and several other atypical antipsychotics that differ in their neurotransmitter receptor affinity profiles are being used for a long-term treatment of schizophrenia. Therefore, understanding of their long-term treatment effects on the expression of antioxidant enzymes and oxidative neural cell injury in rats may be important to explain the possible differential mechanisms underlying their long-term clinical and side effects profiles. The effect of 90 and 180 day exposure to haloperidol (HAL, 2mg/kg/day), a representative typical antipsychotic was compared to exposure to chlorpromazine (CPZ, 10mg/kg/day), ziprasidone (ZIP, 12mg/kg/day), risperidone (RISP, 2.5mg/kg/day), clozapine (CLOZ, 20mg/kg/day) or olanzapine (OLZ, 10mg/kg/day) on the expression of antioxidant defense enzymes and levels of lipid peroxidation in the rat brain. The drug-induced effects on various antioxidant defense enzymes; manganese-superoxide dismutase (MnSOD), copper–zinc superoxide dismutase (CuZnSOD) and catalase (CAT) were assessed by determination of their enzymatic activity and protein content. Immunohistochemical analysis was also carried out to assess the cellular levels of MnSOD and CuZnSOD and cellular morphology. The oxidative membrane damage was assessed by determination of levels of the lipid peroxidation product, hydroxyalkanals (HAEs) in the rat brain. Both 90 and 180 days of HAL treatment very significantly decreased the levels of MnSOD (50%) and CuZnSOD (80%) and increased the levels of HAEs compared to vehicle treatment. Smaller reduction was found in CAT (25%) and no change in the glutathione peroxidase (GSHPx). The levels of enzymatic activity correlated generally well with the levels of enzyme protein indicating that the changes were in the expression of net protein. Though atypical antipsychotics like ZIP, RISP and OLZ did not show any change in the HAEs levels up to 90 days, further treatment up to 180 days resulted in significantly increased levels of HAEs in CPZ, ZIP and RISP, but not in OLZ treated rats. Post-treatment with several atypical antipsychotics (OLZ=CLOZ>RISP) for 90 days after 90 day of HAL treatment significantly restored the HAL-induced loss in MnSOD and CuZnSOD activities and increase in lipid peroxidation products as well as cellular morphology. These data may be very helpful in planning long-term use as well as switch over of these antipsychotics for the management of schizophrenia. [Copyright &y& Elsevier]

Background: The consequences of repeated exposure to psychostimulants have been hypothesized to model aspects of schizophrenia. This experiment assessed the consequences of the administration of an escalating dosing regimen of amphetamine (AMPH) on attentional performance. Fos-like immunoreactivity (Fos-IR) in selected regions of these rats¿ brains was examined to test the hypothesis that AMPH-sensitized attentional impairments are associated with increased recruitment of basal forebrain cholinergic neurons. Methods: Rats were trained in a sustained attention task and then treated with saline or in accordance with an escalating dosing regimen of AMPH (1¿10 mg/kg). Performance was assessed during the pretreatment and withdrawal periods and following the subsequent administration of AMPH ¿challenges¿ (.5, 1.0 mg/kg). Brain sections were double-immunostained to visualize Fos-IR and cholinergic neurons. Results: Compared with the acute effects of AMPH, AMPH ¿challenges,¿ administered over 2 months after the pretreatment was initiated, resulted in significant impairments in attentional performance. In AMPH-pretreated and -challenged animals, an increased number of Fos-IR neurons was observed in the basal forebrain. The majority of these neurons were cholinergic. Conclusions: The evidence supports the hypothesis that abnormally regulated cortical cholinergic inputs represent an integral component of neuronal models of the attentional dysfunctions of schizophrenia. [Copyright &y& Elsevier]

Cholinergic projections to the cortex and hippocampus mediate fundamental cognitive processes. The capacity of the high-affinity choline uptake transporter (CHT) to import choline from the extracellular space to presynaptic terminals is essential for normal acetylcholine synthesis and therefore cholinergic transmission. The CHT is highly regulated, and the cellular mechanisms that modulate its capacity show considerable plasticity. Recent evidence links changes in CHT capacity with the ability to perform tasks that tax attentional processes and capacities. Abnormal regulation of CHT capacity might contribute to the cognitive impairments that are associated with neurodegenerative and neuropsychiatric disorders. Therefore, the CHT might represent a productive target for the development of new pharmacological treatments for these conditions. [ABSTRACT FROM AUTHOR]

Conventional microdialysis methods for measuring acetylcholine (ACh) efflux do not provide sufficient temporal resolution to relate cholinergic transmission to individual stimuli or behavioral responses, or sufficient spatial resolution to investigate heterogeneities in such regulation within a brain region. In an effort to overcome these constraints, we investigated a ceramic-based microelectrode array designed to measure amperometrically rapid changes in extracellular choline as a marker for cholinergic transmission in the frontoparietal cortex of anesthetized rats. These microelectrodes exhibited detection limits of 300 nmfor choline and selectivity (> 100 : 1) of choline over interferents such as ascorbic acid. Intracortical pressure ejections of choline (20 mm, 66–400 nL) and ACh (10 and 100 mm, 200 nL) dose-dependently increased choline-related signals that were cleared to background levels within 10 s. ACh, but not choline-induced signals, were significantly attenuated by co-ejection of the acetylcholinesterase inhibitor neostigmine (Neo; 100 mm). Pressure ejections of drugs known to increase cortical ACh efflux, potassium (KCl; 70 mm, 66, 200 nL) and scopolamine (Scop; 10 mm, 200 nL), also markedly increased extracellular choline signals, which again were inhibited by Neo. Scop-induced choline signals were also found to be tetrodotoxin-sensitive. Collectively, these findings suggest that drug-induced increases in current measured with these microelectrode arrays reflect the oxidation of choline that is neuronally derived from the release and subsequent hydrolysis of ACh. Choline signals assessed using enzyme-selective microelectrode arrays may represent a rapid, sensitive and spatially discrete measure of cholinergic transmission. [ABSTRACT FROM AUTHOR]

Previously we reported that chronic exposure to haloperidol (HAL), but not the atypical antipsychotics risperidone (RISP) or clozapine (CLOZ), resulted in reductions in brain choline acetyltransferase (ChAT) immunoreactivity and impaired water maze task performance in rats. In the present study, we compared the effects of these antipsychotic drugs on the expression of nerve growth factor (NGF) as well ChAT the in the rat cortex and nucleus basalis of Meynert (NBM) in an effort to determine the underlying mechanism for the differential drug effects observed previously. We also evaluated the effects of these compounds in a crossover design to evaluate specific neurochemical consequences of switching between typical and atypical antipsychotics, a common practice observed in the clinical setting. Male Wistar rats (250–300 g) were exposed to HAL (2.0 mg/kg/day), RISP (2.5 mg/kg/day), or CLOZ (20 mg/kg/day) for 45 days or a pre-treatment regimen consisting of administering either RISP/HAL (i.e., RISP followed by HAL) or CLOZ/HAL, or a post-treatment regimen consisting of administering: HAL/RISP or HAL/CLOZ. The duration of each treatment in the crossover study was also 45 days. NGF and ChAT immunoreactivity were measured by quantitative immunohistochemistry in some sub-cerebral cortical regions and NBM after drug exposures. NGF protein was also measured by an enzyme-linked ImmunoSorbent assay (ELISA) in rat sensorimotor cortex. The results indicated that HAL (but not RISP or CLOZ) significantly reduced NGF levels in some sub-cortical regions and ChAT immunoreactivity in both cortex and NBM. However, pre-treatment with CLOZ prevented the HAL-associated decreases in NGF and ChAT, while post-treatment with either RISP or CLOZ (i.e., after the administration of HAL) appeared to restore NGF and ChAT to control levels. These data indicate that antipsychotic drugs exert dissimilar effects on the levels of NGF and ChAT in the brain, which may contribute to their differential effects on cognitive function. The crossover data further suggest that certain atypical antipsychotic drugs (e.g., clozapine) may have the potential to prevent or reverse the deleterious effects of HAL on important neurochemical substrates of cognitive function. [Copyright &y& Elsevier]

Rationale. Recently, we reported that compared to haloperidol, chronic exposure to either the risperidone (RISP) or olanzapine (OLZ) resulted in superior effects on spatial learning performance as well as the cholinergic neurons, although the mechanism for these effects was not addressed. Objectives. The objective of this study was to investigate one plausible mechanism whereby RISP and OLZ exert superior effects on cholinergic neurons, i.e. positive effects on nerve growth factor (NGF), which is known to regulate the brain cholinergic activity as well as cognitive function. Therefore, the effects of chronic exposure to HAL, RISP, or OLZ on the expression of NGF and choline acetyltransferase (ChAT) in the hippocampus (i.e. a brain area well known to be involved in cognitive function and known to receive major cholinergic projections from the medial septum) were compared. Methods. Rats were treated with HAL (1 or 2 mg/kg per day), RISP (1.25 or 2.5 mg/kg per day), or OLZ (5 or 10 mg/kg per day) for 45 days in drinking water. NGF and ChAT were measured by immunohistochemistry and NGF protein was also measured by an enzyme-linked ImmunoSorbent assay. Results. Compared to controls, HAL exposure resulted in a marked reduction in NGF immunoreactivity in the hippocampal dentate gyrus (DG), CA1 and CA3 areas. In contrast, RISP did not alter, while OLZ significantly increased levels of NGF. These changes in NGF levels corresponded well with changes in ChAT immunoreactivity in the hippocampus and the medial septum. Conclusions. These preclinical data, combined with previously published behavioral results, support the premise that OLZ and RISP, in contrast to HAL, preserve cholinergic pathways and cognitive function via superior effects on NGF expression and are thus therapeutically superior for extended use. [ABSTRACT FROM AUTHOR]

Recently, we have reported studies in rats showing that the atypical antipsychotic olanzapine (OLZ), in contrast to haloperidol (HAL), was not associated with reduction of markers of central cholinergic neurons as well as decrements in cognitive performance after chronic exposure. We compared the effect of 45 day chronic exposure of HAL (2 mg/kg per day) to OLZ (10 mg/kg per day) on brain-derived neurotrophic factor (BDNF)) and its high affinity receptor TrkB in rat hippocampus. Since the use of OLZ is presently preferred over HAL in patients, effects of its post-treatment on HAL-induced changes in the expression of BDNF and its TrkB receptor were also investigated. OLZ was administered after 45 days of HAL exposure. HAL, but not OLZ, significantly reduced the levels of BDNF in hippocampus. These changes in BDNF paralleled the levels of TrkB receptors. Furthermore, post-treatment with OLZ markedly restored the HAL treatment associated reductions in both BDNF and TrkB receptors in hippocampus. [Copyright &y& Elsevier]

Nerve growth factor (NGF) has been found to play a crucial role in the neuroplasticity of predominantly cholinergic neurons in brain development, and neuronal survival following brain injury, which reflect in cognitive performance. Wide ranges of neurodevelopmental abnormalities have been reported in schizophrenic patients, who also show poor cognitive performance. We report plasma NGF levels in never-medicated first-episode psychotic (FEP; N=24) and chronic medicated schizophrenic patients (N=24). NGF levels were determined in plasma by Enzyme-Linked ImmunoSorbent Assay (ELISA). Plasma NGF levels were significantly lower in both FEP and medicated chronic patients as compared to normal subjects (P<0.001). However, NGF levels were significantly higher in chronic schizophrenic patients, which were treated with antipsychotics as compared to FEP (P<0.05). Moreover, NGF levels in chronic patients treated with atypical antipsychotics were markedly higher as compared to patients treated with typical antipsychotics (P<0.05). Lower NGF levels in FEP patients at the onset of psychosis may have implications for the neurodevelopmental abnormalities. However, higher NGF levels in chronic patients treated with atypical antipsychotics may have implications for the treatment outcome. [Copyright &y& Elsevier]

Typical and atypical antipsychotics significantly differ in their neurotransmitter receptor affinity profiles, and their efficacy and side effects in schizophrenic patients. Typical antipsychotics have been found to increase the oxidative (i.e. free radical-mediated) cellular injury in rats. Since schizophrenia also involves oxidative injury, the understanding of differential effects of these antipsychotics on expression of antioxidant enzymes and oxidative injury may be very critical. The effect of chronic exposure of haloperidol (HAL), a typical antipsychotic, was compared to effects of risperidone (RIS) or clozapine (CLZ) or olanzapine (OLZ), atypical antipsychotics on antioxidant defense enzymes and lipid peroxidation in the rat brain. The levels of antioxidant enzymes and hydroxyalkenals (HAEs) were measured in rat brain cytosol and fatty acids were measured in brain cell membranes. Chronic HAL treatment for both 45 and 90 days significantly decreased manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) activity with parallel marked increase in (HAEs), a marker of lipid peroxidation in rat brain. The levels of enzymatic activity very well correlated with the levels of enzyme proteins indicating that the changes were probably in the expression of net protein. However, RIS, CLZ and OLZ treatments did not produce any alterations in the levels of antioxidant enzymes and HAEs, both after 45 and 90 days. There were no alterations in the levels of saturated as well as polyunsaturated fatty acids in brain membranes. These findings indicate that chronic administration of HAL, but none of the studied atypicals induce oxidative stress by persistent changes in the levels of antioxidant enzymes and cause membrane lipid peroxidation. [Copyright &y& Elsevier]

Given the increasing prevalence of age-related cognitive decline, it is relevant to consider the factors and mechanisms that might facilitate an individual's resiliency to such deficits. Growing evidence suggests a preeminent role of microglia, the prime mediator of innate immunity within the central nervous system. Human and animal investigations suggest aberrant microglial functioning and neuroinflammation are not only characteristic of the aged brain, but also might contribute to age-related dementia and Alzheimer's Disease. Conversely, accumulating data suggest that modifiable lifestyle factors (MLFs), such as healthy diet, exercise and cognitive engagement, can reliably afford cognitive benefits by potentially suppressing inflammation in the aging brain. The present review highlights recent advances in our understanding of the role for microglia in maintaining brain homeostasis and cognitive functioning in aging. Moreover, we propose an integrated, mechanistic model that postulates an individual's resiliency to cognitive decline afforded by MLFs might be mediated by the mitigation of aberrant microglia activation in aging, and subsequent suppression of neuroinflammation. [ABSTRACT FROM AUTHOR]

Previous research emphasized the impact of traumatic brain injury on cholinergic systems and associated cognitive functions. Here we addressed the converse question: Because of the available evidence indicating cognitive and neuronal vulnerabilities in humans expressing low-capacity cholinergic systems or with declining cholinergic systems, do injuries cause more severe cognitive decline in such subjects, and what cholinergic mechanisms contribute to such vulnerability? Using mice heterozygous for the choline transporter (CHT+/- mice) as a model for a limited cholinergic capacity, we investigated the cognitive and neuronal consequences of repeated, mild concussion injuries (rmCc). After five rmCc, and compared with wild type (WT) mice, CHT+/- mice exhibited severe and lasting impairments in sustained attention performance, consistent with effects of cholinergic losses on attention. However, rmCc did not affect the integrity of neuronal cell bodies and did not alter the density of cortical synapses. As a cellular mechanism potentially responsible for the attentional impairment in CHT+/- mice, we found that rmCc nearly completely attenuated performance-associated, CHT-mediated choline transport. These results predict that subjects with an already vulnerable cholinergic system will experience severe and lasting cognitive-cholinergic effects after even relatively mild injuries. If confirmed in humans, such subjects may be excluded from, or receive special protection against, activities involving injury risk. Moreover, the treatment and long-term outcome of traumatic brain injuries may benefit from determining the status of cholinergic systems and associated cognitive functions. [ABSTRACT FROM AUTHOR]

The synaptic uptake of choline via the high-affinity, hemicholinium-3-dependent choline transporter (CHT) strongly influences the capacity of cholinergic neurons to sustain acetylcholine (ACh) synthesis and release. To advance research on the impact of CHT capacity in humans, we established the presence of the neuronal CHT protein in human T lymphocytes. Next, we demonstrated CHT-mediated choline transport in human T cells. To address the validity of T cell-based choline uptake as a proxy for brain CHT capacity, we isolated T cells from the spleen, and synaptosomes from cortex and striatum, of wild type and CHT-overexpressing mice (CHT-OXP). Choline uptake capacity in T cells from CHT-OXP mice was two-fold higher than in wild type mice, mirroring the impact of CHT over-expression on synaptosomal CHT-mediated choline uptake. Monitoring T lymphocyte CHT protein and activity may be useful for estimating human CNS cholinergic capacity and for testing hypotheses concerning the contribution of CHT and, more generally, ACh signaling in cognition, neuroinflammation and disease. [ABSTRACT FROM AUTHOR]

Stressful life events and stress-related psychiatric disorders impair sustained attention, the ability to monitor rare and unpredictable stimulus events over prolonged periods of time. Despite the link between stress and attentional disruptions, the neurobiological basis for stress regulation of attention systems remains underexplored. Here we examined whether corticotropin releasing factor (CRF), which orchestrates stress responses and is hypersecreted in patients with stress-related psychiatric disorders, impairs sustained attention. To this end, male and female rats received central infusions of CRF prior to testing on an operant sustained attention task (SAT), where rats were trained to discriminate signaled from non-signaled events. CRF caused a dose-dependent decrease in SAT performance in both male and female rats. Females were more impaired than males following a moderate dose of CRF, particularly during the middle part of the session. This sex difference was moderated by ovarian hormones. Females in the estrous cycle stage characterized by lower ovarian hormones had a greater CRF-induced attentional impairment than males and females in other cycle stages. Collectively, these studies highlight CRF as a critical stress-related factor that can regulate attentional performance. As sustained attention subserves other cognitive processes, these studies suggest that mitigating high levels of CRF in patients with stress-related psychiatric disorders may ameliorate their cognitive deficits. [ABSTRACT FROM AUTHOR]

Abstract: Brain-derived neurotrophic factor (BDNF) signaling via tropomyosin-related kinase B (trkB) receptors exerts modulatory effects on glutamatergic transmission, learning, memory and reward processing. Although the role of BDNF in the regulation of mnemonic and affective/motivational processes is well studied, whether this neurotrophin could also regulate executive functions is not known. In the present study, we assessed the effects of intrastriatal infusions on BDNF (1–100 ng/hemisphere) in mice performing an operant strategy set-shifting task that required the animals to eliminate a visual cue-based strategy and adopt a new egocentric spatial response strategy to achieve rewards. Exogenous BDNF administration facilitated the acquisition of strategy shifting by minimizing response perseveration to the previously acquired strategy and this effect resemble an inverted-U shaped dose–response pattern. Faster acquisition of strategy switching in BDNF-infused animals was dependent upon the activation of striatal trkB receptors. Moreover, activation of mGluR2/3 receptors by the selective group II metabotropic receptor agonist LY379268 abolished BDNF-induced cognitive enhancement suggesting the involvement of presynaptic glutamatergic activity. Assessment of striatal glutamate dynamics using electrochemical recordings indicated that local application of BDNF directly induces glutamate release by activating presynaptic trkB receptors on glutamatergic terminals, and this effect followed a bell-shaped dose–response pattern similar to strategy shifting performance. These data suggest that activation of BDNF-trkB signaling in the dorsal striatum improves strategy switching by effectively minimizing response conflicts, and this effect primarily involves facilitation of glutamatergic transmission. [Copyright &y& Elsevier]

Corticoptropin releasing factor (CRF) is implicated in stress-related physiological and behavioral changes. The septohippocampal pathway regulates hippocampal-dependent mnemonic processes, which are affected in stress-related disorders, and given the abundance of CRF receptors in the medial septum (MS), this pathway is influenced by CRF. Moreover, there are sex differences in the MS sensitivity to CRF and its impact on hippocampal function. However, the mechanisms underlying these associations remain elusive. In the present study, we utilized an in vivo biosensor-based electrochemistry approach to examine the impact of MS CRF infusions on hippocampal cholinergic signaling dynamics in male and female rats. Our results show increased amplitudes of depolarization-evoked phasic cholinergic signals in the hippocampus following MS infusion of CRF at the 3 ng dose as compared to the infusion involving artificial cerebrospinal fluid (aCSF). Moreover, a trend for a sex × infusion interaction indicated larger cholinergic transients in females. On the contrary, intraseptal infusion of a physiologically high dose (100 ng) of CRF produced a subsequent reduction in phasic cholinergic transients in both males and females. The assessment of tonic cholinergic activity over 30 min post-infusion revealed no changes at the 3 ng CRF dose in either sex, but a significant infusion × sex interaction indicated a reduction in females at the 100 ng dose of CRF as compared to the aCSF. Taken together, our results show differential, dose-dependent modulatory effects of MS CRF on the dynamics of phasic and tonic modes of cholinergic signaling in the hippocampus of male and female rats. These cholinergic signaling modes are critical for memory encoding and maintaining arousal states, and may underlie sex differences in cognitive vulnerability to stress and stress-related psychiatric disorders. • Low-dose CRF infusion into MS increased phasic ACh release in the hippocampus. • The effects of low-dose CRF on phasic ACh was more prominent in female rats. • High-dose MS CRF suppressed cholinergic transients in both male and female rats. • High- but not low-dose MS CRF affected tonic cholinergic activity in female rats. [ABSTRACT FROM AUTHOR]

Transport of choline via the neuronal high-affinity choline transporter (CHT; SLC5A7) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a common CHT coding substitution (rs1013940; Ile89Val) and reduced attentional control as well as attenuated frontal cortex activation. Here, we used a CRISPR/Cas9 approach to generate mice expressing the I89V substitution and assessed, in vivo, CHT-mediated choline transport, and ACh release. Relative to wild-type (WT) mice, CHT-mediated clearance of choline in male and female mice expressing one or two Val89 alleles was reduced by over 80% in cortex and over 50% in striatum. Choline clearance in CHT Val89 mice was further reduced by neuronal inactivation. Deficits in ACh release, 5 and 10min after repeated depolarization at a low, behaviorally relevant frequency, support an attenuated reloading capacity of cholinergic neurons in mutant mice. The density of CHTs in total synaptosomal lysates and neuronal plasma-membrane-enriched fractions was not impacted by the Val89 variant, indicating a selective impact on CHT function. When challenged with a visual disruptor to reveal attentional control mechanisms, Val89 mice failed to adopt a more conservative response bias. Structural modeling revealed that Val89 may attenuate choline transport by altering conformational changes of CHT that support normal transport rates. Our findings support the view that diminished sustained cholinergic signaling capacity underlies perturbed attentional performance in individuals expressing CHT Val89. The CHT Val89 mouse serves as a valuable model to study heritable risk for cognitive disorders arising from cholinergic dysfunction. [ABSTRACT FROM AUTHOR]

Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective α4β2* nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction with the increased task demands implemented by distractor presentation, the selective agonist, but not nicotine, enhanced the detection of signals during the post-distractor recovery period. This effect is consistent with the hypothesis that second-long increases in cholinergic activity (‘transients’) mediate the detection of cues and that nAChR agonists augment such transients. Electrochemical recordings of prefrontal cholinergic transients evoked by S 38232 and nicotine indicated that the α4β2* nAChR agonist evoked cholinergic transients that were characterized by a faster rise time and more rapid decay than those evoked by nicotine. Blockade of the α7 nAChR ‘sharpens’ nicotine-evoked transients; therefore, we determined the effects of co-administration of nicotine and the α7 nAChR antagonist methyllycaconitine on dSAT performance. Compared with vehicle and nicotine alone, this combined treatment significantly enhanced the detection of signals. These results indicate that compared with nicotine, α4β2* nAChR agonists significantly enhance attentional performance and that the dSAT represents a useful behavioral screening tool. The combined behavioral and electrochemical evidence supports the hypothesis that nAChR agonist-evoked cholinergic transients, which are characterized by rapid rise time and fast decay, predict robust drug-induced enhancement of attentional performance. [ABSTRACT FROM AUTHOR]

Abnormalities in the regulation of neurotransmitter release and/or abnormal levels of extracellular neurotransmitter concentrations have remained core components of hypotheses on the neuronal foundations of behavioral and cognitive disorders and the symptoms of neuropsychiatric and neurodegenerative disorders. Furthermore, therapeutic drugs for the treatment of these disorders have been developed and categorized largely on the basis of their effects on neurotransmitter release and resulting receptor stimulation. This perspective stresses the theoretical and practical implications of hypotheses that address the dynamic nature of neurotransmitter dysregulation, including the multiple feedback mechanisms regulating synaptic processes, phasic and tonic components of neurotransmission, compartmentalized release, differentiation between dysregulation of basal vs activated release, and abnormal release from neuronal systems recruited by behavioral and cognitive activity. Several examples illustrate that the nature of the neurotransmitter dysregulation in animal models, including the direction of drug effects on neurotransmitter release, depends fundamentally on the state of activity of the neurotransmitter system of interest and on the behavioral and cognitive functions recruiting these systems. Evidence from evolving techniques for the measurement of neurotransmitter release at high spatial and temporal resolution is likely to advance hypotheses describing the pivotal role of neurotransmitter dysfunction in the development of essential symptoms of major neuropsychiatric disorders, and also to refine neuropharmacological mechanisms to serve as targets for new treatment approaches. The significance and usefulness of hypotheses concerning the abnormal regulation of the release of extracellular concentrations of primary messengers depend on the effective integration of emerging concepts describing the dynamic, compartmentalized, and activity-dependent characteristics of dysregulated neurotransmitter systems.Neuropsychopharmacology (2007) 32, 1452–1461; doi:10.1038/sj.npp.1301285; published online 13 December 2006 [ABSTRACT FROM AUTHOR]

Cholinergic neurons innervating the cortex have been conceptualized as a major component of the attention system of the brain. Because of recent evidence indicating plastic mechanisms regulating choline transporter (CHT)-mediated high-affinity choline uptake, which is the rate-limiting step of acetylcholine synthesis, the present experiment determined the capacity of cholinergic terminals to transport choline, and the proportion of choline transporters localized in the membrane of synaptic terminals, in several brain regions of rats performing a cognitive vigilance task (CVT) and a simple reaction time task (SRTT) and nonperforming (NP) rats. Compared with evidence from NP rats, increased choline transporter capacity [as indicated by maximum transporter velocity (Vmax)] and an increased density of CHTs situated in synaptic plasma membrane, relative to intracellular locations, were observed in the medial prefrontal cortex of the right but not left hemisphere of CVT-performing animals. Furthermore, right medial prefrontal Vmax, values of CVT-performing rats correlated positively and left medial Vmax values correlated negatively with the animals' performance in signal trials. Measures of CHT function in the brains of SRTT-performing animals did not differ significantly from those in NP rats. The present data support the hypothesis that an increased capacity of choline transporters in the right medial prefrontal cortex, primarily attributable to increased trafficking of transporters from intracellular compartments to the terminal membrane, represents a cellular mechanism contributing to the mediation of attentional performance. [ABSTRACT FROM AUTHOR]

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experiments have even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypical antipsychotics may actually improve cognitive function in some patients, although this assertion requires further investigation. The purpose of this study was to compare the effects of prior chronic (45-or 90-day) oral exposure to HAL and the atypical antipsychotics risperidone (RISP) and clozapine (CLOZ) on cognitive performance and central cholinergic markers in rats. All analyses were done after 4 days of drug washout in order to minimize direct drug effects. Learning performance and choline acetyltransferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypical agents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in several brain regions, including the cortex, caudate-putamen, and hippocampus. ChAT staining in the caudate-putamen and hippocampus was also decreased after 90 days of RISP exposure, raising the possibility of deleterious cognitive effects after exposure to this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effects on central cholinergic neurons and learning performance. [ABSTRACT FROM AUTHOR]

The prefrontal cortex (PFC) governs top–down control of attention and is known to be vulnerable in aging. Cortical reorganization with increased PFC recruitment is suggested to account for functional compensation. Here, we hypothesized that reduced PFC output would exert differential effects on attentional capacities in young and aged rats, with the latter exhibiting a more robust decline in performance. A chemogenetic approach involving designer receptors exclusively activated by designer drugs was utilized to determine the impact of silencing PFC projection neurons in rats performing an operant attention task. Visual distractors were presented in all behavioral testing sessions to tax attentional resources. Under control conditions, aged rats exhibited impairments in discriminating signals with the shortest duration from non-signal events. Surprisingly, chemogenetic inhibition of PFC output neurons did not worsen performance amongst aged animals. Conversely, significant impairments in attentional capacities were observed in young subjects following such manipulation. Given the involvement of PFC-projecting basal forebrain cholinergic neurons in top–down regulation of attention, amperometric recordings were conducted to measure alterations in prefrontal cholinergic transmission in a separate cohort of young and aged rats. While PFC silencing resulted in a robust attenuation of tonic cholinergic signaling across age groups, the capacity to generate phasic cholinergic transients was impaired only amongst young animals. Collectively, our findings suggest a reduced efficiency of PFC-mediated top–down control of attention and cholinergic system in aging, and that activity of PFC output neurons does not reflect compensation in aged rats, at least in the attention domain. [ABSTRACT FROM AUTHOR]

• PFC insult impaired attention in aged rats regardless of cholinergic pruning. • Age-related shifts in PC and OC activity did not correlate with performance. • PC cholinergic pruning altered prefrontal dynamics and weakened attention. • Cholinergic synaptic inputs did not trigger age-related cortical shifts. • Cholinergic system regulated excitation/inhibition balance of reorganized circuits. Cortical remodeling is linked to age-related cognitive changes in humans; however, the mechanisms underlying cortical reorganization in aging remain unknown. Here we examined the consequences of mild cholinergic thinning of the prefrontal cortex (PFC) and parietal cortex (PC) on attention performance-associated changes in cortical activity in young and aged rats. Prefrontal manipulation produced attentional deficits in aged but not young rats regardless of cholinergic pruning. Stereological assessment of c-fos expression revealed age-related reductions in occipital activity and a corresponding increase in PC activity, but these patterns did not correlate with performance. PC cholinergic deafferentation produced opposite changes in PFC recruitment between young and aged rats. Cholinergic pruning reversed the effects of PFC/PC cholinergic manipulations on the activity of CaMKII- and GAD-positive neurons in aged rats. Our results indicate that cortical shifts depend on multiple factors including chronological age, cholinergic changes, and cortical insult, and that cortical reorganization is not necessarily compensatory. Moreover, the cholinergic system modulates excitation/inhibition homeostasis to improve the efficiency of reorganized cortical circuits and stabilize attentional performance. [ABSTRACT FROM AUTHOR]

• Longitudinal cognitive training improved performance of 3xTg and wild-type mice. • Long-term recognition memory at 9 months old was comparable between genotypes. • Cognitive training may compensate for, or prevent, cognitive deficits in 3xTg mice. Preclinical studies in Alzheimer's disease (AD) often rely on cognitively naïve animal models in cross-sectional designs that can fail to reflect the cognitive exposures across the lifespan and heterogeneous neurobehavioral features observed in humans. To determine whether longitudinal cognitive training may affect cognitive capacities in a well-characterized AD mouse model, 3xTg and wild-type mice (n = 20) were exposed daily to a training variant of the Go-No-Go (GNG) operant task from 3 to 9 months old. At 3, 6, and 9 months, performance on a testing variant of the GNG task and anxiety-like behaviors were measured, while long-term recognition memory was also assessed at 9 months. In general, GNG training improved performance with increasing age across genotypes. At 3 months old, 3xTg mice showed slight deficits in inhibitory control that were accompanied by minor improvements in signal detection and decreased anxiety-like behavior, but these differences did not persist at 6 and 9 months old. At 9 months old, 3xTg mice displayed minor deficits in signal detection, and long-term recognition memory capacity was comparable with wild-type subjects. Our findings indicate that longitudinal cognitive training can render 3xTg mice with cognitive capacities that are on par with their wild-type counterparts, potentially reflecting functional compensation in subjects harboring AD genetic mutations. [ABSTRACT FROM AUTHOR]

Nicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine-sired mice, as assessed in a self-administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post-traumatic stress. [ABSTRACT FROM AUTHOR]

The US geriatric population is growing and using more opioids than ever before. The purpose of this study was to determine whether aging influenced the reinforcing efficacy of morphine in male and female rats using a rodent intravenous self-administration paradigm. Male and female aged (20–24 months) and young (2–4 months) Wistar rats were tested at 2 doses of morphine (0.75 mg/kg/infusion and 0.25 mg/kg/infusion). During 10 days of self-administration, aged rats took significantly less morphine than their younger counterparts at the 0.25 mg/kg/infusion dose. Aged males also earned significantly fewer infusions on a progressive ration reinforcement schedule at this dose, suggesting that the reinforcing efficacy of morphine is decreased for this group at this dose. These effects dissipated when a separate group of animals had access to the 0.75 mg/kg/infusion dose for both sexes. Our results indicate that morphine is less reinforcing at lower doses in aged male, but not female rats. This research has potential clinical implications for the chronic treatments involving opioids in aged individuals. • Aging reduced morphine self-administration in male and female Wistar rats. • Aged males had decreased responding on a progressive ratio at low dose of morphine. • At higher dose of morphine, self-administration is unchanged by age. • Aging decreases sensitivity to the reinforcing properties of morphine. [ABSTRACT FROM AUTHOR]

Stress exacerbates symptoms of schizophrenia and attention-deficit/hyperactivity disorder, which are characterized by impairments in sustained attention. Yet how stress regulates attention remains largely unexplored. We investigated whether a 6-day variable stressor altered sustained attention and the cholinergic attention system in male and female rats. Sustained attention was tested with the sustained attention task. Successful performance on the sustained attention task relies on the release of acetylcholine (ACh) into the cortex from cholinergic neurons in the nucleus basalis of Meynert (NBM). Thus, we evaluated whether variable stress (VS) altered the morphology of these neurons with a novel approach using a Cre-dependent virus in genetically modified ChAT::Cre rats, a species used for this manipulation only. Next, electrochemical recordings measured cortical ACh following VS. Finally, we used RNA sequencing to identify VS-induced transcriptional changes in the NBM. VS impaired attentional performance in the sustained attention task and increased the dendritic complexity of NBM cholinergic neurons in both sexes. NBM cholinergic neurons are mainly under inhibitory control, so this morphological change could increase inhibition on these neurons, reducing downstream ACh release to impair attention. Indeed, VS decreased ACh release in the prefrontal cortex of male rats. Quantification of global transcriptional changes revealed that although VS induced many sex-specific changes in gene expression, it increased several signaling molecules in both sexes. These studies suggest that VS impairs attention by inducing molecular and morphological changes in the NBM. Identifying mechanisms by which stress regulates attention may guide the development of novel treatments for psychiatric disorders with attention deficits. [ABSTRACT FROM AUTHOR]

Highlights • Adolescent nicotine exposure increased saccharin reinforcement in adulthood. • Adult nicotine re-exposure biased the sensitivity towards nicotine reward. • Both adolescent and adult nicotine exposure increased impulsive responding. • Adolescent and adult nicotine experience activated distinct behavioral mechanisms. • These mechanisms acted in concert to facilitate maladaptive nicotine taking. Abstract Smokers that begin during adolescence are more likely to develop nicotine dependence than those who begin as adults. However, the factors that contribute to this remain largely unknown. Here we utilized a novel operant oral nicotine self-administration procedure in mice to assess the consequences of adolescent nicotine exposure on nicotine and saccharin (non-drug) reinforcement in adults. Animals were given non-contingent exposure to either saline or nicotine using the osmotic minipumps during both adolescence and adulthood for 2 weeks. Reinforcing efficacy for oral nicotine and saccharin was assessed using the progressive ratio schedule 2-weeks following the washout period in adults. Non-contingent nicotine exposure in adolescence drastically increased operant responding for oral nicotine but reduced responding for oral saccharin in the group re-exposed to nicotine in adulthood. Interestingly, adolescent nicotine-exposed mice that received saline exposure as adults exhibited higher preference for oral saccharin. However, breakpoints for oral nicotine in these mice remained comparable to control animals. Surprisingly, both adolescent and adult nicotine exposure increased inactive lever responding during self-administration presumably reflecting impulsive responding. Our data suggest that adolescent nicotine exposure produces an increase in reinforcement sensitivity in adulthood as reflected by increased saccharin self-administration but this sensitivity becomes biased towards nicotine self-administration when re-exposed to nicotine in adulthood. Moreover, nicotine/saccharin reinforcement could be impacted by changes in cognitive control, such as increased impulsivity. These distinct behavioral mechanisms may act in concert to facilitate maladaptive nicotine taking in smokers that initiate nicotine use during adolescence. [ABSTRACT FROM AUTHOR]

Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh release in vivo compared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured with in vivo microdialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction. [ABSTRACT FROM AUTHOR]

Background Sustained attention, the ability to detect rare and unpredictable events, is central to cognitive performance. This construct can be tested in rodents using a Sustained Attention Task (SAT), where rats are trained to detect an unpredictably occurring signal (a brief light presentation) from non-signal events. The traditional version of this task utilizes an operant chamber with a central panel light for the signal and two retractable response levers. Adaptation of SAT to the increasingly popular touchscreen operant chambers, which do not have levers or fixed lights, could enhance the versatility of the task. New method Here we developed a touchscreen version of SAT where the light signal is presented in the center of the touchscreen, followed by a tone to indicate the beginning of the response period. Rats indicate their choice during this period by touching their nose to one of two touchscreen response areas. The remaining parameters were kept similar to the traditional version. Results Rats acquired touchscreen SAT at a similar rate to the traditional version. As with the traditional version, shorter stimulus durations on the signaled trials reduced accuracy and the presence of a distractor (a flashing houselight) disrupted performance on the touchscreen version. Comparison to existing method Collectively, these data suggest that the touchscreen version is comparable to the traditional version of the SAT, and is an equally valid way of measuring sustained attention. Conclusions Many researchers with touchscreen chambers could easily implement our modifications in order to study sustained attention. [ABSTRACT FROM AUTHOR]

Psychiatric disorders that are characterized by impairments in sustained attention, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and major depression are also sensitive to exacerbation by stress. Sustained attention relies on cholinergic and non-cholinergic projections from the nucleus basalis of Meynert (NBM) in the basal forebrain to the medial prefrontal cortex (mPFC). We have previously shown that central administration of the stress neuropeptide corticotropin releasing factor (CRF) impairs performance on the sustained attention task (SAT) in adult male and female rats. The present study investigated whether this effect was mediated by CRF's action in the NBM. Rats were administered CRF in the NBM and subsequent SAT performance was measured. A high dose of CRF (100 ng) significantly impaired performance on non-signaled events across sex. Because performance on non-signaled events is believed to depend on non-cholinergic (i.e., GABA and glutamate) signaling, high performance liquid chromatography was used to quantify amino acid levels in the NBM and mPFC. We found females have higher levels of glutamate, glutamine, GABA glycine, and alanine in the NBM than males. Importantly, CRF in the NBM led to a local decrease of taurine and several amino acids involved in glutamate synthesis in males and females, changes which may mediate the CRF-induced SAT performance deficit. Together these studies suggest that CRF regulation of amino acids in the NMB contributes to stress-induced attention deficits. • CRF in the NBM impaired sustained attention. • CRF in the NBM decreased NBM levels of amino acids involved in glutamate synthesis. • CRF in the NBM decreased NBM taurine levels. • There are baseline sex differences in mPFC and NBM amino acid levels. • These data suggest CRF disrupts attention by suppressing glutamate and taurine. [ABSTRACT FROM AUTHOR]

In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or “transients”, have been associated with the detection of cues in attention tasks. Here we review four main findings about cholinergic transients during cognitive processing. Cholinergic transients are: (1) associated with the detection of a cue and influenced by cognitive state; (2) not dependent on reward outcome, although the timing of the transient peak co-varies with the temporal relationship between detection and reward delivery; (3) correlated with the mobilization of the cue-evoked response; (4) causal mediators of shifts from monitoring to cue detection. We next discuss some of the key questions concerning the timing and occurrence of transients within the framework of available evidence including: (1) Why does the shift from monitoring to cue detection require a transient? (2) What determines whether a cholinergic transient will be generated? (3) How can cognitive state influence transient occurrence? (4) Why do cholinergic transients peak at around the time of reward delivery? (5) Is there evidence of cholinergic transients in humans? We conclude by outlining future research studies necessary to more fully understand the role of cholinergic transients in mediating cue detection. [ABSTRACT FROM AUTHOR]

Rationale: Deficits in executive functions underlie compulsive drug use, and understanding how nicotine influences these cognitive processes may provide important information on neurobiological substrates of nicotine addiction. Accumulating evidence suggests that β2 subunit-containing nicotinic receptors (nAChRs) are involved in the reinforcing process of nicotine addiction. Whether these nAChRs also contributes to the detrimental effects of chronic nicotine on flexible decision-making is not known. Objectives: In the present study, the effects of chronic nicotine were assessed in mice with partial or complete deletion of the β2 subunit-containing nAChR gene (β2+/− or β2−/−) performing an operant cognitive flexibility task. Results: Visual discrimination learning was not affected in saline-treated β2 nAChR mutants as compared to the wild-type (β2+/+) mice; yet, chronic nicotine facilitated acquisition of visual discrimination in all genotypes. The acquisition of new egocentric response strategy set-shifting remained similar in all genotypes, and there was no effect of treatment. Chronic nicotine treatment impaired reversal learning in β2+/+ mice by increasing response perseveration to the previously rewarded stimulus. Moreover, the acquisition of inverted stimulus-reward contingencies did not differ between β2+/+ and β2−/− mice exposed to chronic nicotine. Interestingly, nicotine-induced reversal learning deficits were not observed in β2+/− mice. Conclusions: Collectively, these findings suggest that β2 subunit-containing nAChRs are not critical for visual discrimination learning and extra dimensional rule shift. However, sustained activation of these nAChRs with nicotine may interfere with inhibitory control processes influencing affective shifts in stimulus-reward contingencies. [ABSTRACT FROM AUTHOR]