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Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) with unknown underlying mechanisms and highly variable responses across subjects. To investigate these issues, we developed a simple computational model. Our model consisted of two neurons linked by an excitatory synapse that incorporates two mechanisms: short-term plasticity (STP) and spike-timing-dependent plasticity (STDP). We applied a variable-amplitude current through I-clamp with a TBS time pattern to the pre- and post-synaptic neurons, simulating synaptic plasticity. We analyzed the results and provided an explanation for the effects of TBS, as well as the variability of responses to it. Our findings suggest that the interplay of STP and STDP mechanisms determines the direction of plasticity, which selectively affects synapses in extended neurons and underlies functional effects. Our model describes how the timing, number, and intensity of pulses delivered to neurons during rTMS contribute to induced plasticity. This not only successfully explains the different effects of intermittent TBS (iTBS) and continuous TBS (cTBS), but also predicts the results of other protocols such as 10 Hz rTMS. We propose that the variability in responses to TBS can be attributed to the variable span of neuronal thresholds across individuals and sessions. Our model suggests a biologically plausible mechanism for the diverse responses to TBS protocols and aligns with experimental data on iTBS and cTBS outcomes. This model could potentially aid in improving TBS and rTMS protocols and customizing treatments for patients, brain areas, and brain disorders. [ABSTRACT FROM AUTHOR]

Arsenic-containing hydrocarbons (AsHCs) are common in marine organisms. However, there is little research on their effects on the central nervous system's advanced activities, such as cognition. Bidirectional synaptic plasticity dynamically regulates cognition through the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the effects of AsHCs on bidirectional synaptic plasticity and the underlying molecular mechanisms remain unexplored. This study provides the first evidence that 15 μg As L−1 AsHC 360 enhances bidirectional synaptic plasticity, occurring during the maintenance phase rather than the baseline phase. Further calcium gradient experiments hypothesize that AsHC 360 may enhance bidirectional synaptic plasticity by affecting calcium ion levels. The enhancement of bidirectional synaptic plasticity by 15 μg As L−1 AsHC 360 holds significant implications in improving cognitive function, treating neuro-psychiatric disorders, promoting neural recovery, and enhancing brain adaptability. [ABSTRACT FROM AUTHOR]

Disruptions in glutamate homeostasis within the mesolimbic reward circuitry may play a role in the pathophysiology of various reward related disorders such as major depressive disorders, anxiety, and substance use disorders. Clear sex differences have emerged in the rates and symptom severity of these disorders which may result from differing underlying mechanisms of glutamatergic signaling. Indeed, preclinical models have begun to uncover baseline sex differences throughout the brain in glutamate transmission and synaptic plasticity. Glutamatergic synaptic strength can be assessed by looking at morphological features of glutamatergic neurons including spine size, spine density, and dendritic branching. Likewise, electrophysiology studies evaluate properties of glutamatergic neurons to provide information of their functional capacity. In combination with measures of glutamatergic transmission, synaptic plasticity can be evaluated using protocols that induce long-term potentiation or long-term depression. This review will consider preclinical rodent literature directly comparing glutamatergic transmission and plasticity in reward related regions of males and females. Additionally, we will suggest which regions are exhibiting evidence for sexually dimorphic mechanisms, convergent mechanisms, or no sex differences in glutamatergic transmission and plasticity and highlight gaps in the literature for future investigation.

Arsenic-containing hydrocarbons (AsHCs) are common in marine organisms. However, there is little research on their effects on the central nervous system’s advanced activities, such as cognition. Bidirectional synaptic plasticity dynamically regulates cognition through the balance of long-term potentiation (LTP) and long-term depression (LTD). However, the effects of AsHCs on bidirectional synaptic plasticity and the underlying molecular mechanisms remain unexplored. This study provides the first evidence that 15 μg As L−1 AsHC 360 enhances bidirectional synaptic plasticity, occurring during the maintenance phase rather than the baseline phase. Further calcium gradient experiments hypothesize that AsHC 360 may enhance bidirectional synaptic plasticity by affecting calcium ion levels. The enhancement of bidirectional synaptic plasticity by 15 μg As L−1 AsHC 360 holds significant implications in improving cognitive function, treating neuro-psychiatric disorders, promoting neural recovery, and enhancing brain adaptability.

Alzheimer's disease (AD) is an incurable, age-related and progressive neurodegenerative disease characterized by cognitive impairments. Deficits in synaptic plasticity were reported in various models of AD-like pathology and are considered as an early contributing factor of cognitive impairment. However, the majority of previous studies were focused on overt, symptomatic stages of pathology and assessed long-term potentiation (LTP), whereas long-term depression (LTD) was much less investigated and the precise nature of its involvement remains poorly defined. To better understand the earliest synaptic dysfunctions along the pre-symptomatic stage of AD-like pathology, we performed a detailed analysis of underlying mechanisms and quantified basal synaptic activity, presynaptic release probability, and synaptic plasticity such as post-tetanic potentiation (PTP), as well as LTP and LTD. These parameters were studied in APPPS1 mouse model at two time points (early- and mid-) along the pre-symptomatic stage, which were compared with alterations monitored at two later time-points, i.e. the onset of cognitive deficits and the overt stage of full-blown pathology. Because sex is known to be an instrumental biological parameter in AD pathophysiology, all alterations were assessed in both males and females. Our data show that, as compared to wild-type (WT) littermates, initial neuronal hyperexcitability, seen at early pre-symptomatic stage shifts subsequently towards hypoexcitability at mid-pre-symptomatic stage and remains impaired at advanced stages. The pre-symptomatic changes also involve increased synaptic plasticity as assessed by paired-pulse facilitation (PPF), which returns to basal level at the onset of pathology and remains stable afterwards. Synaptic plasticity is impaired by mid-pre-symptomatic stage and manifests as lowered LTP and absence of LTD induction, the latter being reported here for the first time. Observed LTP and LTD impairments both persist in older APPPS1 mice. Remarkably, none of the observed differences was gender-dependent. Altogether, our data evidence that major impairments in basal synaptic efficacy and plasticity are detectable already during mid-pre-symptomatic stage of AD-like pathogenesis and likely involve hyperexcitability as the underlying mechanism. Our study also uncovers synaptic alterations that may become critical read-outs for testing the efficiency of novel, pre-symptomatic stage-targeted therapies for AD. • Alzheimer's Disease (AD) displays a long pre-symptomatic stage (PSS). • AD is still incurable since treated late and targeting PSS may be more efficient. • PSS is impossible to assess in human and requires models to identify early targets. • Using a mouse AD model, we identified a novel marker of PSS synaptic dysfunction. • This marker can serve as a read-out for testing efficacy of PSS-targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Neuroplasticity in adolescents is distinct from that of adults. Literature pertaining to neuroplasticity in schizophrenia is limited to adult populations. Aim: We aimed to assess baseline (or resting) cortical excitability and cortical plasticity in adolescents with schizophrenia using the transcranial magnetic stimulation-electromyography (TMS-EMG) protocol. Methods: Twenty adolescent cases with schizophrenia and 20 age and gender matched healthy controls were studied using a crossover design. Single pulse TMS elicited resting motor threshold (RMT) and motor evoked potentials (MEPs) were assessed. Cortical plasticity was determined by tracking MEPs after a single session continuous theta burst stimulation (cTBS) and intermittent theta burst stimulation (iTBS) up to 120 min at 12 intervals. Results: Baseline (or resting) cortical excitability was found to be significantly lower in cases compared with controls. Response patterns to cTBS and iTBS were similar between the crossover. While cTBS led to inhibitory response, iTBS had an excitatory effect in both the groups. In the cases, while cTBS led to significantly greater initial inhibitory response, iTBS led to significantly lower excitatory response, compared with controls. The time taken to return to baseline excitability was significantly longer after receiving cTBS for cases, compared with controls. Conclusions: iTBS and cTBS lead to excitatory and inhibitory response, representing classical long-term depression and long-term potentiation effects, respectively, in both cases and controls. We conclude that adolescents with schizophrenia have significantly lower baseline (resting) cortical excitability as well as significantly greater inhibitory plasticity; excitatory plasticity is significantly lower. [ABSTRACT FROM AUTHOR]

The hippocampus-prefrontal cortex (HPC-PFC) pathway plays a fundamental role in executive and emotional functions. Neurophysiological studies have begun to unveil the dynamics of HPC-PFC interaction in both immediate demands and long-term adaptations. Disruptions in HPC-PFC functional connectivity can contribute to neuropsychiatric symptoms observed in mental illnesses and neurological conditions, such as schizophrenia, depression, anxiety disorders, and Alzheimer's disease. Given the role in functional and dysfunctional physiology, it is crucial to understand the mechanisms that modulate the dynamics of HPC-PFC communication. Two of the main mechanisms that regulate HPC-PFC interactions are synaptic plasticity and modulatory neurotransmission. Synaptic plasticity can be investigated inducing long-term potentiation or long-term depression, while spontaneous functional connectivity can be inferred by statistical dependencies between the local field potentials of both regions. In turn, several neurotransmitters, such as acetylcholine, dopamine, serotonin, noradrenaline, and endocannabinoids, can regulate the fine-tuning of HPC-PFC connectivity. Despite experimental evidence, the effects of neuromodulation on HPC-PFC neuronal dynamics from cellular to behavioral levels are not fully understood. The current literature lacks a review that focuses on the main neurotransmitter interactions with HPC-PFC activity. Here we reviewed studies showing the effects of the main neurotransmitter systems in long- and short-term HPC-PFC synaptic plasticity. We also looked for the neuromodulatory effects on HPC-PFC oscillatory coordination. Finally, we review the implications of HPC-PFC disruption in synaptic plasticity and functional connectivity on cognition and neuropsychiatric disorders. The comprehensive overview of these impairments could help better understand the role of neuromodulation in HPC-PFC communication and generate insights into the etiology and physiopathology of clinical conditions. [ABSTRACT FROM AUTHOR]

The hippocampus-prefrontal cortex (HPC-PFC) pathway plays a fundamental role in executive and emotional functions. Neurophysiological studies have begun to unveil the dynamics of HPC-PFC interaction in both immediate demands and long-term adaptations. Disruptions in HPC-PFC functional connectivity can contribute to neuropsychiatric symptoms observed in mental illnesses and neurological conditions, such as schizophrenia, depression, anxiety disorders, and Alzheimer’s disease. Given the role in functional and dysfunctional physiology, it is crucial to understand the mechanisms that modulate the dynamics of HPC-PFC communication. Two of the main mechanisms that regulate HPC-PFC interactions are synaptic plasticity and modulatory neurotransmission. Synaptic plasticity can be investigated inducing long-term potentiation or long-term depression, while spontaneous functional connectivity can be inferred by statistical dependencies between the local field potentials of both regions. In turn, several neurotransmitters, such as acetylcholine, dopamine, serotonin, noradrenaline, and endocannabinoids, can regulate the fine-tuning of HPC-PFC connectivity. Despite experimental evidence, the effects of neuromodulation on HPC-PFC neuronal dynamics from cellular to behavioral levels are not fully understood. The current literature lacks a review that focuses on the main neurotransmitter interactions with HPC-PFC activity. Here we reviewed studies showing the effects of the main neurotransmitter systems in long- and short-term HPC-PFC synaptic plasticity. We also looked for the neuromodulatory effects on HPC-PFC oscillatory coordination. Finally, we review the implications of HPC-PFC disruption in synaptic plasticity and functional connectivity on cognition and neuropsychiatric disorders. The comprehensive overview of these impairments could help better understand the role of neuromodulation in HPC-PFC communication and generate insights into the etiology and physiopathology of clinical conditions.

Quadripulse stimulation (QPS) is a newly developed stimulation method to induce neural plasticity in humans. One stimulation burst consisting of four monophasic pulses is given every 5 s for 30 min. A total of 360 bursts (1440 pulses) are given in one session. Short-interval QPS potentiates the target cortical excitability and long-interval QPS depresses it. QPS at an inter-pulse interval of 5 ms (QPS5) induces long-term potentiation (LTP)-like effects most efficiently and QPS50 induces long-term depression (LTD)-like effects most effectively in the primary motor cortex. In this mini-review, we briefly introduce QPS: (i) principle and cortical plasticity (stimulators and protocols, synaptic plasticity, underlying mechanisms, meta-plasticity, axonal plasticity, and drug effects), (ii) robust and strong neural plasticity induction (variability, influence of phasic muscle contraction, independency of BDNF polymorphism, sensory cortical plasticity, neural plasticity in the contralateral hemisphere, on-line effects on the brain networks, studies of normal brain physiology, and visuomotor sequence learning), (iii) therapeutic applications to neurological and psychiatric disorders (Parkinson's disease, epilepsy, cerebrovascular disease, and major depression), (iv) safety, and (v) future issues. Based on this evidence, we propose that QPS is currently the most powerful and reliable non-invasive brain stimulation method to induce neural plasticity in humans. [ABSTRACT FROM AUTHOR]

In this paper, we propose a complex neuro-memristive synapse that exhibits the physiological acts of synaptic potentiation and depression of the human-brain. Specifically, the proposed neuromorphic synapse efficiently imitates the synaptic plasticity, especially long-term potentiation (LTP) and depression (LTD), and short-term facilitation (STF) and depression (STD), phenomena of a biological synapse. Similar to biological synapse, the short- or long-term potentiation (STF and LTP) or depression (STD or LTD) of the memristive synapse are distinguished on the basis of time or repetition of input cycles. The proposed synapse is also designed to exhibit the effect of reuptake and neurotransmitters diffusion processes of a bio-synapse. In addition, it exhibits the distinct bio-realistic attributes, i.e., strong stimulation, exponentially decaying conductance trace of synapse, and voltage dependent synaptic responses, of a neuron. The neuro-memristive synapse is designed in SPICE and its bio-realistic functionalities are demonstrated via various simulations.

Homeostatic plasticity is a stabilizing mechanism commonly observed in real neural systems that allows neurons to maintain their activity around a functional operating point. This phenomenon can be used in neuromorphic systems to compensate for slowly changing conditions or chronic shifts in the system configuration. However, to avoid interference with other adaptation or learning processes active in the neuromorphic system, it is important that the homeostatic plasticity mechanism operates on time scales that are much longer than conventional synaptic plasticity ones. In this paper we present an ultralow leakage circuit, integrated into an automatic gain control scheme, that can implement the synaptic scaling homeostatic process over extremely long time scales. Synaptic scaling consists in globally scaling the synaptic weights of all synapses impinging onto a neuron maintaining their relative differences, to preserve the effects of learning. The scheme we propose controls the global gain of analog log-domain synapse circuits to keep the neuron's average firing rate constant around a set operating point, over extremely long time scales. To validate the proposed scheme, we implemented the ultralow leakage synaptic scaling homeostatic plasticity circuit in a standard 0.18 $\mu$m complementary metal-oxide-semiconductor process, and integrated it in an array of dynamic synapses connected to an adaptive integrate and fire neuron. The circuit occupies a silicon area of 84  $\mu$m $\times$ 22 $\mu$m and consumes approximately 10.8 nW with a 1.8 V supply voltage. We present experimental results from the homeostatic circuit and demonstrate how it can be configured to exhibit time scales of up to 100 ks, thanks to a controllable leakage current that can be scaled down to 0.45 aA (2.8 electrons per second). [ABSTRACT FROM PUBLISHER]

Synaptic connectivity forms the basis for neuronal communication and the storage of information. Experiences and learning of new abilities can drive remodelling of this connectivity and promotes the formation of spine clusters; dendritic segments with a higher spine density. Spines located within these segments are frequently co-activated, undergo different dynamics than synapses located outside of this dendritic compartment and have, in general, a longer lifetime. Several lines of evidence have shown that chemical synapses located close to each other share or compete for intracellular signalling molecules and structural resources. This sharing and competition directly influences spine dynamics. Spines can grow, shrink, increase or decrease the surface expression of receptors, channels and adhesion molecules or remain stable and unchanged over extended periods of time. Here we summarize recent discoveries and provide a closer look at spine clustering, dendritic segment-specific signalling and potential molecular mechanisms underlying associative and heterosynaptic plasticity. [ABSTRACT FROM AUTHOR]

Adolescents are especially prone to drug addiction, but the underlying biological basis of their increased vulnerability remains unknown. We reveal that translational control by phosphorylation of the translation initiation factor eIF2α (p-eIF2α) accounts for adolescent hypersensitivity to cocaine. In adolescent (but not adult) mice, a low dose of cocaine reduced p-eIF2α in the ventral tegmental area (VTA), potentiated synaptic inputs to VTA dopaminergic neurons, and induced drug-reinforced behavior. Like adolescents, adult mice with reduced p-eIF2α-mediated translational control were more susceptible to cocaine-induced synaptic potentiation and behavior. Conversely, like adults, adolescent mice with increased p-eIF2α became more resistant to cocaine's effects. Accordingly, metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD)—whose disruption is postulated to increase vulnerability to drug addiction—was impaired in both adolescent mice and adult mice with reduced p-eIF2α mediated translation. Thus, during addiction, cocaine hijacks translational control by p-eIF2α, initiating synaptic potentiation and addiction-related behaviors. These insights may hold promise for new treatments for addiction.

Long-term depression (LTD) and long-term potentiation (LTP)-like plasticity are models of synaptic plasticity which have been associated with memory and learning. The induction of LTD and LTP-like plasticity, using different stimulation protocols, has been proposed as a means of addressing abnormalities in cortical excitability associated with conditions such as focal hand dystonia and stroke. The aim of this study was to investigate whether the excitability of the cortical projections to the tibialis anterior muscle could be decreased when dorsiflexion of the ankle joint was imagined and paired with peripheral electrical stimulation of the nerve supplying the antagonist soleus muscle. The effect of stimulus timing was evaluated by comparing paired stimulation timed to reach the cortex before, at and after the onset of imagined movement. Fourteen healthy subjects participated in six experimental sessions held on non-consecutive days. The timing of stimulation delivery was determined offline based on the contingent negative variation (CNV) of electroencephalography (EEG) brain data obtained during imagined dorsiflexion. Afferent stimulation was provided via a single pulse electrical stimulation to the peripheral nerve paired, based on the CNV, with motor imagination of ankle dorsiflexion. A significant decrease (P=0.001) in the excitability of the cortical projection of tibialis anterior was observed when the afferent volley from the electrical stimulation of the tibial nerve (TN) reached the cortex at the onset of motor imagination based on the CNV. When TN stimulation was delivered before (P=0.62), or after (P=0.23) imagined movement onset there was no significant effect. Nor was a significant effect found when electrical stimulation of the TN was applied independent of imagined movement (P=0.45). Therefore, the excitability of the cortical projection to a muscle can be inhibited when electrical stimulation of the nerve supplying the antagonist muscle is precisely paired with the onset of imagined movement.

Transcranial magnetic stimulation (TMS) is a non-invasive, non-pharmacological technique that is able to modulate cortical activity beyond the stimulation period. The residual aftereffects are akin to the plasticity mechanism of the brain and suggest the potential use of TMS for therapy. For years, TMS has been shown to transiently improve symptoms of neuropsychiatric disorders, but the underlying neural correlates remain elusive. Recently, there is evidence that altered connectivity of brain network dynamics is the mechanism underlying symptoms of various neuropsychiatric illnesses. By combining TMS and electroencephalography (EEG), the functional connectivity patterns among brain regions, and the causal link between function or behaviour and a specific brain region can be determined. Nonetheless, the brain network connectivity are highly complex and involve the dynamics interplay among multitude of brain regions. In this review article, we present previous TMS-EEG co-registration studies, which explore the functional connectivity patterns of human cerebral cortex. We argue the possibilities of neural correlates of long-term potentiation/ depression (LTP-/LTD)-like mechanisms of synaptic plasticity that drive the TMS aftereffects as shown by the dissociation between EEG and motor evoked potentials (MEP) cortical output. Here, we also explore alternative explanations that drive the EEG oscillatory modulations post TMS. The precise knowledge of the neurophysiological mechanisms underlying TMS will help characterise disturbances in oscillatory patterns, and the altered functional connectivity in neuropsychiatric illnesses. [ABSTRACT FROM AUTHOR]

Objective In patients with benign myoclonus epilepsy (ME), giant sensory-evoked potential (SEP) reflects the hyperexcitability of the sensory cortex. The aim of this study was to compare the effect of quadripulse transcranial magnetic stimulation (QPS) on the median nerve SEP between ME patients and healthy subjects. Methods Ten healthy volunteers and six ME patients with giant SEP participated in this study. QPSs at interpulse intervals (IPIs) of 5, 30, 50, 100, 500 and 1250 ms were applied over the left primary motor cortex (M1) for 30 min. The peak-to-peak amplitudes of N20 to P25 (N20–P25) and P25 to N33 (P25–N33) components were measured at the left somatosensory cortex. Results In healthy participants, the P25–N33 was bidirectionally modulated by QPS over M1, following the Bienenstock–Cooper–Munro (BCM) theory. The N20–P25 was not affected by any QPSs. In ME patients, the giant P25–N33 was potentiated after any QPSs. Furthermore, the N20–P25 was also potentiated after QPS at IPIs of 5, 30, 50 100 or 500 ms. Conclusions In ME patients, the cascade for long-term depression-like effects may be impaired. Significance The giant SEP was furthermore enhanced by QPS. [ABSTRACT FROM AUTHOR]

Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity.

Background Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson’s disease and in l -3,4-dihydroxyphenylalanine ( l -DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson’s disease. Methods Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured. Results We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK. Conclusions These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA. [ABSTRACT FROM AUTHOR]

Abstract: Endogenous cannabinoids play important roles in a variety of functions in the mammalian brain, including the regulation reward-related information processing. The primary mechanism through which this is achieved is the presynaptic modulation of synaptic transmission. During reward- and reinforcement-related behavior dopamine levels increase in forebrain areas and this has recently been shown to be modulated by the endocannabinoid system. Therefore, understanding how endocannabinoids are mobilized to modulate synaptic inputs impinging on midbrain dopamine neurons is crucial to a complete understanding of the roles that these molecules play in reward behavior, drug abuse and addiction. Here we summarize the literature describing short-term and long-term regulation of afferent connections on dopamine neurons in the ventral tegmental area via endocannabinoid activation of cannabinoid CB1 receptors, and describe the mechanisms through which these molecules are released during reward-based behavior and exposure to abused drugs. [Copyright &y& Elsevier]

Highlights: [•] Peripheral injection of 5% formalin or CFA induced discharges of the C-fibers. [•] The C-fiber-evoked field potentials induced spinal LTP within 3h. [•] Low- and high-frequency electric stimulation of the sciatic nerve induced spinal LTP. [•] TRPV1 receptor antagonists CPZ or AMG 9810 inhibited the LTP induction. [ABSTRACT FROM AUTHOR]

Highlights: [•] Neuronal nitric oxide synthase is necessary for phrenic long-term facilitation (pLTF) following acute intermittent hypoxia. [•] Episodic spinal NO is sufficient to elicit facilitation of phrenic nerve activity (pMF). [•] NO-induced pMF involves 5-HT2B receptors and spinal NADPH oxidase activity. [ABSTRACT FROM AUTHOR]

Highlights: [•] EPSP–IPSP interaction induces plasticity in convergent excitatory and inhibitory inputs. [•] EPSP–IPSP interaction induces differential modifications in competitive MCs. [•] Plasticity in competitive MCs displays distinct requirements on NMDAR activity. [ABSTRACT FROM AUTHOR]

Abstract: It is known that lipopolysaccharide (LPS) treatment induces neuroinflammation and memory deterioration. One of the mechanisms may be the interference with brain-derived neurotrophic factor (BDNF) gene expression and function. Lipopolysaccharide (3μg/kg and 10μg/kg) was unilaterally injected into the substantia nigra of adult male Wistar rats. Pergolide-induced rotational behavior test was employed to validate unilateral damage to the dopamine nigrostriatal neurons. Anxiety–depression-like behaviors were studied by means of elevated plus-maze task and forced swimming test, as animal models of anxiety and depression. Rats given LPS exhibited the following: decrease of the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming and increase of immobility times within forced swimming test. In addition, these behaviors are associated with decreased BDNF mRNA expression in rat hippocampus. Taken together, these data indicate that intranigral LPS infusion influences the induction of BDNF mRNA expression within hippocampus which contributes to observed behavioral responses in rats, with relevance for Parkinson's disease conditions. [Copyright &y& Elsevier]

Highlights: [•] Actin cytoskeleton and its regulatory proteins are needed for memory formation. [•] Actin cytoskeleton and its regulatory proteins are essential for synaptic plasticity. [•] Actin cytoskeleton is involved in synaptic transmission and neuronal morphogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction. [Copyright &y& Elsevier]

Highlights: [•] Saturating levels of LTP and LTD were induced in slices of the lateral amygdala. [•] Maximum LTP and LTD determine the extent of the synaptic modification range. [•] Maternal separation stress shrank the modification range in the thalamic input. [•] Maternal separation enhanced LTD in the cortical input. [•] Altered synaptic plasticity will have consequences for amygdala-dependent learning. [ABSTRACT FROM AUTHOR]

Highlights: [•] Can animal models be used for studying affective and cognitive comorbidities of pain? [•] How does pain interact with its comorbidities in the animals? [•] What are the underlying mechanisms of pain comorbidities in the animals? [Copyright &y& Elsevier]

Abstract: Eukaryotic elongation factor 2 kinase (eEF2K) is a member of the small group of atypical ‘α-kinases’. It phosphorylates and inhibits eukaryotic elongation factor 2, to slow down the elongation stage of protein synthesis, which normally consumes a great deal of energy and amino acids. The activity of eEF2K is normally dependent on calcium ions and calmodulin. eEF2K is also regulated by a plethora of other inputs, including inhibition by signalling downstream of anabolic signalling pathways such as the mammalian target of rapamycin complex 1. Recent data show that eEF2K helps to protect cancer cells against nutrient starvation and is also cytoprotective in other settings, including hypoxia. Growing evidence points to roles for eEF2K in neurological processes such as learning and memory and perhaps in depression. [Copyright &y& Elsevier]

Highlights: [•] RanBP9 overexpression decreases dendritic arbor in the cortex and hippocampus. [•] RanBP9 reduced spine density at 12 months of age but not at 6months. [•] Decreased spine density correlated well with the reduced levels of phospho-cofilin. [•] Reduced spine density provided the physical basis for the loss of synaptic proteins. [Copyright &y& Elsevier]

Abstract: While the importance of epigenetic mechanisms is well established for numerous aspects of cell differentiation and development, recent findings have shown epigenetic processes to be a critical regulatory component in postmitotic neurons. Particularly intriguing, and potentially significant, are data demonstrating epigenetic regulation of cognitive behaviors. Different aspects of learning and memory appear to be regulated at the level of epigenetic chromatin modifications. Furthermore, it is becoming clear that the dysfunction of epigenetic mechanisms can lead to various disorders accompanied by significant mental impairment. Here, we review the evidence for the epigenetic control of cognition and the role of epigenetic dysregulation in mental disorders. A better understanding of epigenetic mechanisms will increase our fundamental knowledge of cognition and also provide new and exciting avenues of treatment for various mental disorders. [Copyright &y& Elsevier]

Highlights: [•] Memantine rescued hippocampal-dependent memory and hippocampal LTD in JDM rats. [•] LTD was impaired by a malfunction in NR2B-containing NMDA receptors in JDM rats. [•] Abnormal NMDA receptor function was caused by excessive PKA activity in JDM rats. [Copyright &y& Elsevier]

Highlights: [•] Excitotoxicity is a primary mechanism of neuronal injury following stroke. [•] Excitotoxicity requires influx of calcium ion through the NMDA receptor. [•] Different subpopulations of the NMDA receptor elicit distinct functional output. [•] NMDA receptor promotes neuronal death or survival depending on what's downstream. [•] Studying downstream signaling events allows development of better stroke treatments. [ABSTRACT FROM AUTHOR]

Abstract: A subgroup of anticonvulsant and neuroleptic drugs acts through the potentiation of GABA pathways. The regulatory role of GABA in neuronal circuit formation is related to its depolarizing action that supports activity-dependent synaptogenesis. We hypothesized that elevated levels of GABA in the immature brain modify synaptogenesis in excitatory synapses and consequently affect mice behavior. In support of this theory, we showed previously that neonatal exposure to a GABA-transaminase inhibitor (Vigabatrin, GVG) modifies the expression of presynaptic proteins and suppresses excitatory synaptic potentials. To further characterize this phenomenon, we examined the effect of GVG applied during postnatal days 4–14, during the switch in GABA function from a depolarizing to a hyperpolarizing substance, on the development of excitatory synapses and mice sociability. Early exposure to GVG induced differential effects on synaptic proteins in the hippocampus and the cerebral cortex, including the downregulation of GluR1/GluR2 and NR2A/NR2B ratios in the hippocampus cytoplasm, a minute effect on the regulatory proteins CAMKII and PKA in the cerebral cortex, and increases in pGluR1, CAMKII, PKA and Reelin levels. Early GVG exposure was also associated with region specific regulation of monoamines, reduction in hippocampal DA, and enhancement of cortical NE levels. Age-dependent modified sociability and lack of preference for social interactions were observed in mice treated with GVG. Overall, early life exposure to GVG is expected to alter cortico-hippocampal axis connectivity and balance due to the different effects GVG has on key synaptic proteins in the associated brain regions, thus potentially causing behavioral impairment. [Copyright &y& Elsevier]