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Emotionally motivated behaviors rely on the coordinated activity of descending neural circuits involved in motor and autonomic functions. Using a pseudorabies (PRV) tract-tracing approach in typically behaving rats, our group previously identified descending premotor, presympathetic, and dual-labeled premotor-presympathetic populations throughout the central rostral-caudal axis. The premotor-presympathetic populations are thought to integrate somatomotor and sympathetic activity. To determine whether these circuits are dysregulated in subjects with altered emotional regulation, subsequent neuroanatomical analyses were performed in male subjects of two distinct genetic models relevant to clinical depression and anxiety: the Wistar Kyoto (WKY) rat and selectively bred Low Novelty Responder (bLR) rat. The present study explored alterations in premotor efferents from locus coeruleus (LC) and subdivisions of the periaqueductal grey (PAG), two areas involved in emotionally motivated behaviors. Compared to Sprague Dawley rats, WKY rats had significantly fewer premotor projections to hindlimb skeletal muscle from the LC and from the dorsomedial (DMPAG), lateral (LPAG), and ventrolateral (VLPAG) subdivisions of PAG. Relative to selectively bred High Novelty Responder (bHR) rats, bLR rats had significantly fewer premotor efferents from LC and dorsolateral PAG (DLPAG). Cumulatively, these results demonstrate that somatomotor circuitry in several brain areas involved in responses to stress and emotional stimuli are altered in rat models with depression-relevant phenotypes. These somatomotor circuit differences could be implicated in motor-related impairments in clinically depressed patients. [ABSTRACT FROM AUTHOR]

Research characterizing the neuronal substrate of anxiety has implicated different brain areas, including the medial septal nucleus (m-SEPT). Previous reports indicated a role of dopamine and nitric oxide (NO) in anxiety-related behaviors. In this study, the extracellular single-unit recording was performed from the m-SEPT in adult male albino Wistar rats. Baseline activity was recorded for 5 min, and the post-injection recording was performed for another 5 min after the microinjection of each drug. The results showed that (1) both D1- and D2-like receptor agonists (SKF-38393 and quinpirole) enhanced the firing rate of m-SEPT neurons; (2) both D1- and D2-like antagonists (SCH-23390 and sulpiride) attenuated the firing rate of m-SEPT neurons; (3) l-arginine (NO precursor) increased the firing rate of m-SEPT neurons, but a non-specific NOS inhibitor, l-NAME, elicited no significant alterations; (4) the non-specific NOS inhibitor reversed the enhanced firing rate produced by SKF-38393 and quinpirole; (5) neither of the dopaminergic antagonists changed the enhanced activity resulted from the application of the NO precursor. These results contribute to our understanding of the complex neurotransmitter interactions in the m-SEPT and showed that both dopaminergic and NO neurotransmission are involved in the modulation of the firing rate of neurons in the m-SEPT. [ABSTRACT FROM AUTHOR]

Skeletal muscles embed multiple tendon organs, both at the proximal and distal ends of muscle fibers. One of the functions of such spatial distribution may be to provide locally unique force feedback, which may become more important when stresses are distributed non-uniformly within the muscle. Forces exerted by connections between adjacent muscles (i.e. epimuscular myofascial forces) may cause such local differences in force. The aim of this exploratory study was to investigate the effects of mechanical interactions between adjacent muscles on sensory encoding by tendon organs. Action potentials from single afferents were recorded intra-axonally in response to ramp-hold release (RHR) stretches of a passive agonistic muscle at different lengths or relative positions of its passive synergist. The tendons of gastrocnemius (GAS), plantaris (PL) and soleus (SO) muscles were cut from the skeleton for attachment to servomotors. Connective tissues among these muscles were kept intact. Lengthening GAS + PL decreased the force threshold of SO tendon organs (p = 0.035). The force threshold of lateral gastrocnemius (LG) tendon organs was not affected by SO length (p = 0.371). Also displacing LG + PL, kept at a constant muscle–tendon unit length, from a proximal to a more distal position resulted in a decrease in force threshold of LG tendon organs (p = 0.007). These results indicate that tendon organ firing is affected by changes in length and/or relative position of adjacent synergistic muscles. We conclude that tendon organs can provide the central nervous system with information about local stresses caused by epimuscular myofascial forces. [ABSTRACT FROM AUTHOR]

Recent animal and human studies connected the Morc family CW-type zinc finger 1 (Morc1) gene with early life stress and depression. Moreover, the Morc superfamily is related to epigenetic regulation in diverse nuclear processes. So far, the Morc1 gene was mainly studied in spermatogenesis, whereas its distribution and function in the brain are still unknown. In a first attempt to characterize Morc1 in the brain, we performed a Western Blot analysis as well as a real-time PCR analysis during different stages of development. Additionally, we detected Morc1 mRNA using real-time PCR in different mood-regulating brain areas in adult rats. We found that MORC1 protein as well as Morc1 mRNA is already expressed in the brain at embryonic day 14 and is stably expressed until adulthood. Furthermore, Morc1 mRNA is present in many important brain areas of mood regulation like the medial prefrontal cortex, the nucleus accumbens, the hippocampus, the hypothalamus, and the amygdala. The ample distribution in the brain and its molecular structure as a zinc finger protein indicate that Morc1 might act as a transcription factor. This function and its expression in mood-regulating areas already in the early brain development turn Morc1 into a possible candidate gene for mediating early life stress and depression. [ABSTRACT FROM AUTHOR]

After hindlimb unloading (HU), the adaptive changing of the rat step cycle duration, kinematics of the ankle and knee joints, and duration of one-joint ankle extensor m. soleus (SOL) activity are detected. However, how the activity of their synergist gastrocnemius medialis muscle (GM) changes in locomotion after HU remains unknown. GM is a two-joint muscle that produces both extension and flexion torques at the ankle and knee, respectively, regardless of the step cycle phase. The aim of our study was to assess changes in the flexor and extensor activity of GM and their influence on hindlimb kinematics after HU. The hindlimb kinematics, activity of GM, and SOL were evaluated, and semitendinosus muscle (ST) activity was registered in six Wistar rats in treadmill locomotion before and after HU. The mean EMG of the GM activity, which was co-active with ST burst activity, significantly increased after HU. The mean EMG of the GM activity, which was co-active with SOL activity, was unchanged after HU, but both SOL and GM bursts had a tendency to increase in duration. Hyperextension of the knee joint and the tendency to overextension of the ankle joint in the late of the stance phase were revealed after HU. The results show that the absence of weight bearing leads to an increase only in the flexor activity of GM and does not affect the extensor GM activity. Possible mechanisms of changes in GM activity and joint kinematics after HU are discussed. [ABSTRACT FROM AUTHOR]

The medial septum (MS) is an important modulator of hippocampal function. The degree of damage in which the particular set of septo-hippocampal projections contributes to the deficits of spatial memory with concomitant changes of hippocampal receptors expression has not been studied till present. Therefore, we investigated spatial memory and the expression level of cholinergic (α7 nACh and M1), GABAergic (α1 subunit of GABAA) and glutamatergic (NR2B subunit of NMDA and GluR 1 subunit of AMPA) receptors in the hippocampus following selective lesions of cholinergic and GABAergic septo-hippocampal projection. Learning process and long-term spatial memory were assessed using a Morris water maze. The obtained results revealed that in contrast to cholinergic lesions, rats with MS GABAergic lesions exhibit a retention deficit in 3 days after training. Western blot analyses revealed the MS cholinergic lesions have significant effect on the expression level of the M1 mACh receptors, while MS GABAergic lesions induce dramatic modulations of hippocampal glutamatergic, cholinergic and GABAergic receptors expression. These results for the first time demonstrated that selective lesions of MS cholinergic and GABAergic neurons differentially affect long-term spatial memory and the memory deficit after MS GABAergic lesion is paralleled with significant changes of hippocampal glutamate, GABA and acetylcholine receptors expression. [ABSTRACT FROM AUTHOR]

Despite extensive preclinical and clinical investigations, a clinically relevant neuroprotective agent against oxaliplatin-induced peripheral neuropathy, which affects the quality of life following chemotherapy, has not been identified. Epidemiological data suggest that ibuprofen may reduce the risk of neuropathy. Male rats were treated with oxaliplatin (n = 6), oxaliplatin and ibuprofen (n = 5) or vehicle (n = 5) every second day for 15 days. Neuropathy was evaluated using mechanical detection thresholds (MDT) at the hind paw and sensory nerve conduction velocity (SNCV) in the tail nerve at baseline, right after and 3 weeks after the end of treatment. Intraepidermal nerve fibre density (IENFD) was evaluated in the hind paw and inflammation in the dorsal root ganglia 3 weeks after treatment. Inflammation in the dorsal root ganglia was assessed using quantitative real-time RT-PCR (qPCR) of the mRNA levels for the pro-inflammatory cytokines, TNF-α and IL-1β, and by immunohistochemical staining for Iba1+ macrophages. SNCV was reduced in rats treated with oxaliplatin and with oxaliplatin and ibuprofen compared to control rats 3 weeks after treatment. No differences were found for MDT 3 weeks after treatment. IENFD was reduced in rats treated with oxaliplatin. There was a trend towards up-regulation of TNF-α mRNA levels in rats treated with oxaliplatin and with oxaliplatin and ibuprofen. Morphological changes of Iba1+ macrophages suggested activation, but no differences were found in area fraction or size of macrophage cell bodies. The results did not support a neuroprotective effect of ibuprofen but indicated that inflammation may play a role in oxaliplatin-induced peripheral neuropathy. [ABSTRACT FROM AUTHOR]

It has been previously demonstrated that the Me5 nucleus is involved in the genesis of reflex activities at whisker pad level. Specific Me5 neurons, which provide sensory innervation of the macrovibrissae, are monosynaptically connected with small hypoglossal neurons innervating the extrinsic muscles that control macrovibrissal movements. Artificial whisking, induced by the electrical stimulation of the peripheral stump of the facial nerve and the electrical stimulation of the XII nucleus or the infraorbital nerve, induced evoked responses in the whisker pad extrinsic motor units, along with a significant increase in the electromyographic activity of the extrinsic pad muscles (Mameli et al. in Acta Oto-Laryngol 126:1334-1338, 2006; in Pfűgers Arch Eur J Physiol 456:1189-1198, 2008; in Brain Res 1283:34-40, 2009; in Exp Brain Res 234:753-761, 2016). In anaesthetized rats, we evaluated the possible involvement of this Me5-XII loop in the genesis of rhythmical whisking. The anatomical findings showed that in addition to the ipsilateral, even the contralateral Me5 nucleus could be retrogradely labeled by the Dil tracer injected into the whisker pad of one side, they, furthermore, showed labeled axons extending across the midline between the two nuclei. The electrophysiological findings agreed with the neuroanatomical results, since the mechanical or artificially induced deflection of the whiskers of one side, evoked in the Me5 contralateral nucleus different patterns of responses. The hypothesis that the Me5-XII loops, along with their cross-linked relationship, could act as a “central generator” responsible for the stereotyped symmetrical pattern of macrovibrissal movements such as rhythmical whisking has been discussed. [ABSTRACT FROM AUTHOR]

Ghrelin, a gastrointestinal hormone, is a modulator of the sense of smell. The main source of ghrelin in the central nervous system has been mainly observed in specific populations of hypothalamic neurons. An increasing number of studies have reported ghrelin synthesis and its effect on neurons outside the hypothalamus. Ghrelin and its receptors are expressed in the olfactory bulbs and in other centres of the brain, such as the amygdala, for processing olfactory signals, pyramidal neurons of the cerebral cortex and the dorsal vagal complex of the medulla oblongata. It is known that ghrelin is involved in cognitive mechanisms and eating behaviours, in fact, its expression increases in anticipation of food intake. In order to identify the existence of centrifugal direct afferents from the main olfactory bulb to the medial amygdala and the hypothalamus arcuate nucleus, in this work we used two retrograde tracers, Dil and Fluoro Gold, and immunohistochemical procedure to visualize positive ghrelin neurons. Our paper provides neuroanatomic support for the ghrelin modulation of smell. Our results show that ghrelin neuron projections from mitral cells of bulbs can transmit olfactory information via branching connections to the amygdala and the hypothalamus. This pathway could play an important role in regulating feeding behaviour in response to odours. [ABSTRACT FROM AUTHOR]

Little is known about the reasons for occurrence of facial nerve palsy after removal of cerebellopontine angle tumors. Since the intra-arachnoidal portion of the facial nerve is considered to be so vulnerable that even the slightest tension or pinch may result in ruptured axons, we tested whether a graded stretch or controlled crush would affect the postoperative motor performance of the facial (vibrissal) muscle in rats. Thirty Wistar rats, divided into five groups (one with intact controls and four with facial nerve lesions), were used. Under inhalation anesthesia, the occipital squama was opened, the cerebellum gently retracted to the left, and the intra-arachnoidal segment of the right facial nerve exposed. A mechanical displacement of the brainstem with 1 or 3 mm toward the midline or an electromagnet-controlled crush of the facial nerve with a tweezers at a closure velocity of 50 and 100 mm/s was applied. On the next day, whisking motor performance was determined by video-based motion analysis. Even the larger (with 3 mm) mechanical displacement of the brainstem had no harmful effect: The amplitude of the vibrissal whisks was in the normal range of 50°-60°. On the other hand, even the light nerve crush (50 mm/s) injured the facial nerve and resulted in paralyzed vibrissal muscles (amplitude of 10°-15°). We conclude that, contrary to the generally acknowledged assumptions, it is the nerve crush but not the displacement-induced stretching of the intra-arachnoidal facial trunk that promotes facial palsy after cerebellopontine angle surgery in rats. [ABSTRACT FROM AUTHOR]

Previous studies performed in rats showed that the whisker-pad motor innervation involves not only the facial nerve, but also some hypoglossal neurons whose axons travel within the trigeminal infraorbital nerve (ION) and target the extrinsic muscles surrounding the whisker-pad macrovibrissae. Furthermore, the electrical stimulation of the ION induced an increase in the EMG activity of these muscles, while the hypoglossal nucleus stimulation elicited evoked potentials and single motor unit responses. However, the existence of a neural network able to involve the XIIth nucleus in macrovibrissae whisking control was totally unknown until now. Since other recent experiments demonstrated that: (1) the mesencephalic trigeminal nucleus (Me5) neurons respond to both spontaneous and artificial movements of macrovibrissae, and (2) the Me5 peripheral terminals provide a monosynaptic sensory innervation to the macrovibrissae, the present study was aimed at analyzing a possible role of the Me5 nucleus as a relay station in the sensory-motor loop that involves the XIIth nucleus neurons in rhythmic whisking control. Two tracers were used in the same animal: Fluoro Gold, which was injected into the whisker pad to retrogradely label the hypoglossal whisker-pad projection neurons, and Dil, which was instead injected into the Me5 to label its projections to these hypoglossal neurons. Results demonstrated that terminals of the Me5 neurons monosynaptically target the hypoglossal whisker-pad projection neurons. The functional role of this sensory-motor connection is discussed, with particular regard to a hypothesized proprioceptive reflex in whisker-pad extrinsic muscles that can be elicited by the activation of the Me5 macrovibrissae receptors. [ABSTRACT FROM AUTHOR]

Evidence suggests that there are positive effects of exercise on learning and memory. Moreover, some studies have demonstrated that forced exercise plays the role of a stressor. This study was aimed at investigating the effects of different timing of exercise and exercise withdrawal on memory, and serum and hippocampal corticosterone (CORT) levels. Wistar rats were randomly divided into five groups: control, sham, exercise-rest (exercise withdrawal), rest-exercise (exercised group), and exercise-exercise (continuous exercise). Rats were forced to run on a treadmill for 1 h/day at a speed 20-21-m/min. Memory function was evaluated by the passive avoidance test in different intervals (1, 7 and 21 days) after foot shock. Findings showed that after the exercise withdrawal, short-term and mid-term memories, had significant enhancement compared to the control group, while the long-term memory did not present this result. In addition, the serum and hippocampal CORT levels were at the basal levels after the rest period in the exercise-rest group. In the rest-exercise group, exercise improved mid- and long-term memories, whereas continuous exercise improved all types short-, mid- and long-term memories, particularly the mid-term memory. Twenty-one and forty-two days of exercise significantly decreased the serum and hippocampal CORT levels. It seems that exercise for at least 21 days with no rest could affect biochemical factors in the brain. Also, regular continuous exercise plays an important role in memory function. Hence, the duration and withdraw of exercise are important factors for the neurobiological aspects of the memory responses. [ABSTRACT FROM AUTHOR]

This study was designed to investigate the metabosensitive afferent response evoked by electrically induced fatigue (EIF), lactic acid (LA) and potassium chloride (KCl) in three muscle types. We recorded the activity of groups III-IV afferents originating from soleus, gastrocnemius and tibialis anterior muscles. Our data showed a same pattern of response in the three muscles after chemical injections, i.e., a bell curve with maximal discharge rate at 1 mM for LA injections and a linear relationship between KCl concentrations and the afferent discharge rate. Furthermore, a stronger response was recorded after EIF in the gastrocnemius muscle compared to the two other muscles. The change in afferent discharge after 1 mM LA injection was higher for the gastrocnemius muscle compared to the response obtained with the corresponding concentration applied in the two other muscles, whereas changes to KCl injections did not dramatically differ between the three muscles. We conclude that anatomical (mass, phenotype, vascularization, receptor and afferent density...) and functional (flexor vs. extensor) differences between muscles could explain the amplitude of these responses. [ABSTRACT FROM AUTHOR]

Sleep abnormalities, such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of posttraumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stressor exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops. SPS resulted in acute increases in REM sleep and transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. Reductions in theta (4-10 Hz) and sigma (10-15 Hz) band power during transition to REM sleep also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. [ABSTRACT FROM AUTHOR]

Dopaminergic signaling within the primary motor cortex (M1) is necessary for successful motor skill learning. Dopaminergic neurons projecting to M1 are located in the ventral tegmental area (VTA, nucleus A10) of the midbrain. It is unknown which behavioral correlates are encoded by these neurons. The objective here is to investigate whether VTA-M1 fibers are collaterals of projections to prefrontal cortex (PFC) or nucleus accumbens (NAc) or if they form a distinct pathway. In rats, multiple-site retrograde fluorescent tracers were injected into M1, PFC and the core region of the NAc and VTA sections investigated for concomitant labeling of different tracers. Dopaminergic neurons projecting to M1, PFC and NAc were found in nucleus A10 and to a lesser degree in the medial nucleus A9. Neurons show high target specificity, minimal collateral branching to other than their target area and hardly cross the midline. Whereas PFC- and NAc-projecting neurons are indistinguishably intermingled within the ventral portion of dopaminergic nuclei in middle and caudal midbrain, M1-projecting neurons are only located within the dorsal part of the rostral midbrain. Within M1, the forelimb representation receives sevenfold more dopaminergic projections than the hindlimb representation. This strong rostro-caudal gradient as well as the topographical preference to dorsal structures suggest that projections to M1 emerged late in the development of the dopaminergic systems in and form a functionally distinct system. [ABSTRACT FROM AUTHOR]

Cancer chemotherapy is associated with the development of numerous adverse effects, including nausea, emesis and other alterations in gastrointestinal (GI) motility. The administration of 5-HT receptor antagonists has provided a clinical advance in the treatment of chemotherapy-induced vomiting but these drugs lose efficacy throughout chronic treatment. The effects of these drugs in experimental animals under chronic administration are not well known. Our aim was to study, using radiographic methods, the effect of the 5-HT receptor antagonist granisetron on GI dysmotility induced in the rat by repeated cisplatin administration. First, invasive methods were used to select a dose of granisetron capable of reducing increased stomach weight due to acute cisplatin administration (6 mg/kg, ip). Second, rats received two intraperitoneal (ip) injections once a week for 4 weeks: granisetron (1 mg/kg, ip) or saline and, thirty min later, saline or cisplatin (2 mg/kg, ip). Body weight gain was measured throughout treatment. Radiological techniques were used to determine the acute (after first dose) and chronic (after last dose) effects of cisplatin and/or granisetron on GI motility. Repeated cisplatin-induced weight loss which granisetron did not prevent. Gastric emptying was delayed after the first cisplatin administration. Granisetron completely prevented this effect. After weekly administration, cisplatin-induced gastric dysmotility was enhanced and granisetron was not capable of completely preventing this effect. Granisetron prevents gastric emptying alterations, but its efficacy decreases throughout antineoplastic treatment. This might be due to the enhanced effect of cisplatin. [ABSTRACT FROM AUTHOR]

Cancer patients undergoing chemotherapy continue to experience the debilitating side effect of nausea associated with their treatment. Although acute and delayed vomiting have become well managed with the advent of the 5-hydroxytryptamine-3 antagonists, such as ondansetron, and the neurokinin-1 receptor antagonists (such as aprepitant), nausea is still a relatively unmanaged adverse side effect of chemotherapy treatment. When nausea and vomiting are not properly managed, patients are at a greater risk of developing anticipatory nausea (AN)-a conditional association between chemotherapy-related treatment cues, such as the clinic environment, and the subsequent nausea experienced. Once it develops, AN is refractive to pharmacological treatment with classic antiemetics. Currently, non-specific antianxiety drugs (benzodiazepines) are prescribed; however, their sedating side effects are undesirable. Here, we review the animal models of AN that have been developed. These preclinical models have aided researchers in the evaluation of potentially efficacious pharmacological treatments for AN. Accumulating evidence using animal models demonstrates that cannabinoid compounds effectively reduce AN, without producing sedation. These results highlight the need for human clinical trials evaluating the efficacy of these compounds. [ABSTRACT FROM AUTHOR]

The study aimed at determining changes in a course of motoneuronal afterhyperpolarization (AHP) and in contractile twitches of motor units (MUs) during activity evoked by increasing number of stimuli (from 1 to 5), at short interspike intervals (5 ms). The stimulation was applied antidromically to spinal motoneurones or to isolated axons of MUs of the medial gastrocnemius muscle within two separate series of experiments on anesthetized rats. Alterations in the amplitude and time parameters of the AHP of successive spikes were compared to changes in force and time course of successive twitches obtained by mathematical subtraction of tetanic contractions evoked by one to five stimuli. The extent of changes of the studied parameters depended on a number of applied stimuli. The maximal modulation of the AHP and twitch parameters (a prolongation and an increase in the AHP and twitch amplitudes) was typically observed after the second pulse, while higher number of pulses at the same frequency did not induce so prominent changes. One may conclude that changes observed in parameters of action potentials of motoneurons are concomitant to changes in contractile properties of MU twitches. This suggests that both modulations of the AHP and twitch parameters reflect mechanisms leading to force development at the beginning of MU activity. [ABSTRACT FROM AUTHOR]

We examined the effects of hippocampal (HPC) damage on odour recognition memory, using a novel odour recognition task that was adapted from the more common novel object recognition task. Three separate experiments were conducted. In Experiment 1, we tested rats in novel odour recognition across different retention intervals (i.e. 15 min, 24 h, 1 week, 5 weeks). Given a single acquisition session, rats' performance deteriorated after 24 h, but given multiple acquisition sessions (i.e. four sessions over 2 days), rats were able to perform well after retention intervals up to 5 weeks. In Experiment 2, we examined the possible anterograde amnesic effects of HPC damage on novel odour recognition, finding that pre-training damage to the entire HPC failed to cause amnesia for retention delays extending up to 5 weeks. In Experiment 3, we examined whether post-training HPC damage would cause retrograde amnesia, but failed to find any evidence of an impairment. The combined results suggest that the neural network supporting odour recognition is independent of the HPC. [ABSTRACT FROM AUTHOR]

The unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle induces hemiparkinsonism in rats and is a well established animal model of Parkinson's disease. In this study, we assessed the spontaneous activity of substantia nigra pars reticulata (SNr) neurons in unilateral 6-OHDA- or sham-treated rats. Extracellular single cell recordings revealed a bilaterally decreased firing rate in short-term 6-OHDA-lesioned rats (8-10 weeks post lesion) while no rate differences were evident in long-term lesioned animals (5-8 months post lesion) in vivo under chloral hydrate anaesthesia. However, firing pattern of the SNr neurons (indicated by interspike interval (ISI) histogram parameters: coefficient of variation, skewness and kurtosis) was significantly altered only after long-term lesion: 53.8 % of the recorded cells in the ipsilateral 6-OHDA-lesioned SNr fired in a bursting pattern (compared to 5.9-16.7 % in contralateral SNr or sham controls). Additionally, behavioural effects of the lesion were assessed 4 weeks post lesion by the forelimb adjusting stepping test. A decreased number of adjusting steps with the contralateral forepaw, as well as an increased performance with the ipsilateral paw was found for the 6-OHDA-lesioned rats as compared to sham controls. Furthermore, stepping values were negatively correlated with the ISI parameters after long-term lesion, while there were no correlations with the short-term groups. Firing rate was not correlated regardless of the time frame. In conclusion, long-term changes in firing pattern may represent a neuronal correlate of the 6-OHDA-induced hemiparkinsonism and may be useful for the interpretation of 6-OHDA-induced motor deficits and compensatory mechanisms as well. [ABSTRACT FROM AUTHOR]

While decline in vocal quality is prevalent in an aging population, the underlying neurobiological mechanisms contributing to age-related dysphonia are unknown and difficult to study in humans. Development of an animal model appears critical for investigating this issue. Using an established aging rat model, we evaluated if 50-kHz ultrasonic vocalizations in 10, 32-month-old (old) Fischer 344/Brown Norway rats differed from those in 10, 9-month-old (young adult) rats. The retrograde tracer, Cholera Toxin β, was injected to the thyroarytenoid muscle to determine if motoneuron loss in the nucleus ambiguus was associated with age. Results indicated that older rats had vocalizations with diminished acoustic complexity as demonstrated by reduced bandwidth, intensity, and peak frequency, and these changes were dependent on the type of 50-kHz vocalization. Simple calls of old rats had reduced bandwidth, peak frequency, and intensity while frequency-modulated calls of old rats had reduced bandwidth and intensity. Surprisingly, one call type, step calls, had increased duration in the aged rats. These findings reflect phonatory changes observed in older humans. We also found significant motoneuron loss in the nucleus ambiguus of aged rats, which suggests that motoneuron loss may be a contributing factor to decreased complexity and quality of ultrasonic vocalizations. These findings suggest that a rat ultrasonic phonation model may be useful for studying age-related changes in vocalization observed in humans. [ABSTRACT FROM AUTHOR]

Cortical spreading depression (CSD) is influenced by brain excitability and is related to neurological diseases, such as epilepsy. In vitro evidence indicates that neuronal electrical activity is potentiated after CSD. Malnutrition can cause electrophysiological changes in the brain, both in animals and in humans. Here, we investigated in vivo whether CSD potentiates the amplitude of electrocorticogram (ECoG) and of transcallosal evoked responses in adult well-nourished (W), early-malnourished (M), and food-restricted rats. ECoG amplitudes were compared before and after CSD, at two parietal regions (designated the anterior and posterior regions). In the anterior region, post-CSD amplitudes of the ECoG waves were 13-23% higher ( P < 0.05) than the pre-CSD values in all groups. In the posterior region, amplitudes increased 22% in the M group only ( P < 0.05). In a fourth CSD-free group, ECoG amplitude did not change during the four recording hours. Transcallosal electrically evoked cortical responses also increased 21.5 ± 9.6% and 41.8 ± 28.5%, after CSD, in the W and M conditions, respectively, as compared to pre-CSD values. The data support the hypothesis of an in vivo CSD potentiation on cortical excitability as recorded by spontaneous and evoked electrical activity and modulation by nutritional status. [ABSTRACT FROM AUTHOR]

A lower than expected tetanic force (the tetanic depression) is regularly observed in fast motor units (MUs) when a higher stimulation frequency immediately follows a lower one. The aim of the present study was to determine whether prolongation of only the first interpulse interval (IPI) resulted in tetanic depression. The experiments were carried out on fast MUs of the medial gastrocnemius muscle in cats and rats. The tetanic depression was measured in each case as the force decrease of a tetanus with one IPI prolonged in relation to the tetanic force at the respective constant stimulation frequency. Force depression was observed in all cases studied and was considerably greater in cats. For cats, the mean values of force depression amounted to 28.64% for FR and 10.86% for FF MUs whereas for rats 9.30 and 7.21% for FR and FF motor units, respectively. Since the phenomenon of tetanic depression in mammalian muscle is commonly observed even after a change in only the initial interpulse interval within a stimulation pattern, it can effectively influence processes of force regulation during voluntary activity of a muscle, when motoneurones progressively increase the firing rate. [ABSTRACT FROM AUTHOR]

When motor units are discharging tonically, transient excitatory synaptic inputs produce an increase in the probability of spike occurrence and also increase the instantaneous discharge rate. Several researchers have proposed that these induced changes in discharge rate and probability can be used to estimate the amplitude of the underlying excitatory post-synaptic potential (EPSP). We tested two different methods of estimating EPSP amplitude by comparing the amplitude of simulated EPSPs with their effects on the discharge of rat hypoglossal motoneurons recorded in an in vitro brainstem slice preparation. The first estimation method (simplified-trajectory method) is based on the assumptions that the membrane potential trajectory between spikes can be approximated by a 10 mV post-spike hyperpolarization followed by a linear rise to the next spike and that EPSPs sum linearly with this trajectory. We hypothesized that this estimation method would not be accurate due to interspike variations in membrane conductance and firing threshold that are not included in the model and that an alternative method based on estimating the effective distance to threshold would provide more accurate estimates of EPSP amplitude. This second method (distance-to-threshold method) uses interspike interval statistics to estimate the effective distance to threshold throughout the interspike interval and incorporates this distance-to-threshold trajectory into a threshold-crossing model. We found that the first method systematically overestimated the amplitude of small (<5 mV) EPSPs and underestimated the amplitude of large (>5 mV EPSPs). For large EPSPs, the degree of underestimation increased with increasing background discharge rate. Estimates based on the second method were more accurate for small EPSPs than those based on the first model, but estimation errors were still large for large EPSPs. These errors were likely due to two factors: (1) the distance to threshold can only be directly estimated over a limited portion of the interspike interval and (2) the distance to threshold can be affected by the EPSP itself. Both methods provide the most accurate EPSP estimates for EPSP amplitudes less than 5 mV and moderate background discharge rates (~15 imp/s). [ABSTRACT FROM AUTHOR]

It is unknown whether the rodent visual system can perceive biological motion, an ability present in primates, cats, and several bird species. Using a water-maze visual discrimination task, we find that rats can be trained to distinguish between left- and rightward motion of abstract point-light displays of walking humans. However, rats were unable to generalize to a novel point-light display (a walking cat), or to a display of a backward walking human, where overall body configuration and local, ballistic foot motion provide directly opposing cues regarding movement direction. Together, these experiments provide the first demonstration of the ability of rodents to extract motion direction cues from abstract, point-light displays. However, when isolated, neither the overall body configuration nor the local motion of the feet appears to provide sufficient information for rats to reliably extract movement direction in biological motion displays. [ABSTRACT FROM AUTHOR]

A doublet of action potentials is frequently observed at the beginning of motoneuronal discharge patterns and its appearance leads to a considerable increase in the motor unit force. The aims of this study were (1) to determine the relationship between the intensity of rectangular depolarization currents injected into motoneurones and their ability to generate doublets and (2) to evaluate the influence of the initial doublets on changes in motoneuronal firing frequency. Experiments were performed on anesthetized rats, and recordings were taken from motoneurones located in the L4–L5 segments of the spinal cord. The depolarization current necessary to evoke the initial doublet of action potentials was measured and expressed in multiples of the rheobase. A gradual increase in the intensity of current injected into motoneurones resulted in initial doublets in 80% of the cases studied, at doublet threshold ranges between 1.25 and 4.0 times the rheobase. This suggests that doublets are an effect of strong synaptic excitation of motoneurones that may precede a sudden change in force during a movement. Moreover, in the great majority of the studied motoneurones, this initial doublet caused changes in the subsequent firing rate by the prolongation of the first interspike interval. [ABSTRACT FROM AUTHOR]

There is no established treatment for the long-term effects produced by perinatal asphyxia. Thus, we investigated the neuroprotection provided by nicotinamide against the effects elicited by perinatal asphyxia on hippocampus and behaviour observed at 30–90 days of age. Asphyxia was induced by immersing foetuses-containing uterine horns, removed from ready-to-deliver rats into a water bath at 37°C for 20 min. Caesarean-delivered siblings were used as controls. Saline or nicotinamide (0.8 mmol/kg, i.p.) was administered to control and asphyxia-exposed animals 24, 48, and 72 h after birth. The animals were examined for morphological changes in hippocampus, focusing on delayed cell death and mossy fibre sprouting, and behaviour, focusing on cognitive behaviour and anxiety. At the age of 30–45 days, asphyxia-exposed rats displayed (1) increased apoptosis, assessed in whole hippocampus by nuclear Hoechst staining, and (2) increased mossy fibre sprouting, restricted to the stratum oriens of dorsal hippocampus, assessed by Timm’s staining. Rats from the same cohorts displayed (3) deficits in non-spatial working memory, assessed by a novel object recognition task, and (4) increased anxiety, assessed by an elevated plus-maze test when examined at the age of 90 days. Nicotinamide prevented the effects elicited by perinatal asphyxia on apoptosis, working memory, and anxiety. [ABSTRACT FROM AUTHOR]

Brain injury during the last trimester to the first 1–4 years in humans is now thought to trigger an array of intellectual and emotional problems later in life, including disorders such as schizophrenia. In adult schizophrenic brains, there is a specific loss of neurons that co-express glutamic acid decarboxylase-parvalbumin (GAD67-PV). Loss of this phenotype is thought to occur in mature animals previously exposed to N-methyl- d-aspartate receptor (NMDAR) antagonists during late gestation or at postnatal day 7 (P7). However, in similarly treated animals, we have previously shown that GAD67 and PV are unaltered in the first 24 h. To more precisely define when changes in these markers first occur, we exposed rat pups (P7 or P6–P10) to the NMDAR antagonist MK801 and at P11 co-stained brain sections for GAD67 or PV. In the cingulate cortex, we found evidence for a reduction in PV (GAD67 levels were very low to undetectable). In contrast, in the somatosensory cortex, we found that expression of GAD67 was reduced, but PV remained stable. Further, repeated but not single doses of MK801 were necessary to see such changes. Thus, depending on the region, NMDAR antagonism appears to influence expression of PV or GAD67, but not both. These observations could not have been predicted by previous studies and raise important questions as to how the GAD67-PV phenotype is lost once animals reach maturity. More importantly, such differential effects may be of great clinical importance, given that cognitive deficits are seen in children exposed to anesthetics that act by blocking the NMDAR. [ABSTRACT FROM AUTHOR]

In contrast to somatosensory cortex (SI), where the pervasiveness of reorganizational capacities is well-established, plasticity of receptive fields (RFs) of adult primary visual cortex (VI) remains controversial. To investigate RF plasticity in VI of adult rats, we here used intracortical microstimulation (ICMS) to overcome particularities related to stimulus presentation and training procedures which limit comparison across modalities. Our results show that VI RFs can be altered by ICMS; however, changes depended on the pre-ICMS RF size. Initially small RFs expanded after 2 h of ICMS with little signs of recovery within the next hours, while initially large RFs remained unaffected. Inspection of the time course of neuron responses revealed, however, that in large RFs early response components were enhanced, while late response components were reduced resulting in changes of the spatiotemporal RF properties. Although plastic changes in VI showed a substantial heterogeneity, our results indicate a capacity of VI neurons to undergo plastic changes comparable to SI neurons. However, the magnitude and aspects of reversibility appeared to be different suggesting a significant modality-specificity of reorganizational changes of cortical sensory neurons. [ABSTRACT FROM AUTHOR]

Altering dopamine synaptic transmission can affect both cranial and limb sensorimotor function, but often to a different degree of severity. We hypothesized that haloperidol has dose-dependent but differential effects on lingual forces, lingual movement rates, and limb movement initiation. We measured average and maximal lingual force, tongue press rate and cataleptic descent time in nine Fischer 344/Brown Norway rats in varied doses of haloperidol. Decreases in lingual force and temporal parameters and increases in cataleptic descent time were related to haloperidol dose. However, they were related to a different degree as the relationships were strong between average force and tongue press rate, moderate between maximal force and tongue press rate, moderate between average force and cataleptic descent time, and weak between maximal force and cataleptic descent time. Elucidating the relationships between the cranial and limb sensorimotor systems in the context of altered dopamine synaptic transmission may assist in developing therapies for conditions such as Parkinson’s disease. [ABSTRACT FROM AUTHOR]

Endonuclease G is a mitochondrial enzyme, known to be translocated to the nucleus after transient focal cerebral ischemia and contribute to DNA degradation. After global cerebral ischemia, delayed cell death is observed in the thalamic reticular nucleus but the mechanisms involved are not well described. The purpose of this study was to identify if Endonuclease G was expressed in the cell nucleus of parvalbumin+ GABA’ergic neurons in relation to cell death after global cerebral ischemia in the thalamic reticular nucleus. The cell death in male Wister rats were studied from 6 h until 4 days after global cerebral ischemia induced by transient 2-vessel carotid occlusion with hypotension for 15 min. Hematoxylin–eosin staining and immunohistochemistry for Endonuclease G, Parvalbumin and Glial fibrillary acidic protein was performed after the ischemic insult. Eosinophilic neurons and vacuolization of the cytoplasm in parvalbumin+ neurons were observed 2 days after ischemia. Endonuclease G immunoreactivity increased in the cytoplasm 12 h after ischemia and was translocated to the nucleus of parvalbumin+ neurons after 24 h. In the nucleus of astroglia, Endonuclease G was expressed after 2 days with an apoptotic-like morphology and the number of Endonuclease G-expressing astroglia increased during the later time points. During the same period the number of parvalbumin+ neurons decreased. In conclusion, this study has identified that Endonuclease G is translocated from the cytoplasm to the nucleus of neurons and expressed with apoptotic-like morphology in the nucleus of astroglia in the thalamic reticular nucleus after global cerebral ischemia. [ABSTRACT FROM AUTHOR]

A large body of clinical evidence suggests a possible association between perinatal asphyxia and the onset of early, as well as long-term, neurological and psychiatric disorders including cognitive deficits. The present study investigated cognitive and motor function modifications in a well characterized and clinically relevant experimental rat model of human perinatal asphyxia. The results reported here show that adult rats exposed to a single (20 min) asphyctic episode at delivery displayed: (a) a deficit in non-spatial memory, assessed in a novel object recognition task; (b) an impaired motor coordination, measured by the rotarod test. On the other hand, gross motor activity and spatial memory, evaluated in both the Y maze and the Barnes maze, were not affected by perinatal asphyxia. The results of this study provide further insights into the long-term effects of perinatal asphyxia on neurobehavioural functions. [ABSTRACT FROM AUTHOR]

Many motor rehabilitation therapies are based on principles of motor learning. Motor learning depends on preliminary knowledge of the trained and other (similar) skills. This study sought to investigate the influence of prior skill knowledge on re-learning of a precision reaching skill after a cortical lesion in rat. One group of animals recovered a previously known skill (skill training, followed by stroke and re-learning training, TST, n = 8). A second group learned the skill for the first time after stroke (ST, n = 6). A control group received prolonged training without stroke ( n = 6). Unilateral partial motor cortex lesions were induced photothrombotically after identifying the forelimb representation using epidural stimulation mapping. In TST animals, re-learning after stroke was slower than learning before stroke (post hoc repeated measures ANOVA P = 0.039) and learning in the control group ( P = 0.033). De novo learning after stroke (ST group) was not different from healthy learning. These findings show that skill learning can be performed if the motor cortex is partially lesioned; re-learning of a skill after stroke is slowed by prior knowledge of the skill. It remains to be tested in humans whether task novelty positively influences rehabilitation therapy. [ABSTRACT FROM AUTHOR]

Recordings of the electroencephalogram (EEG) are regularly used to asses the severity of transient global ischaemia in rats. Here, we investigated whether the EEG obtained from electrodes placed in the hippocampus does indeed give valuable information about the consequences of an ischaemic event. Furthermore, we evaluated how evoked synaptic responses from the same electrodes placed in the hippocampal CA1 area changed with time and in relation to damage. We performed transient two vessel-occlusion with hypobaric hypotension in rats to induce selective, delayed neuronal death in CA1. Beforehand, the animals had been chronically implanted with electrodes. Stimulating electrodes had been placed into the Schaffer collaterals and recording electrodes into the CA1 area. EEG was recorded from shortly before ischaemia until up to 40 min post-ischaemia. Field excitatory post-synaptic potentials (fEPSP) were recorded before ischaemia or sham-operation and 2 and 7 days afterwards. We found a significant negative correlation between the duration of the EEG amplitude decrease (flattening) and the number of surviving neurons in CA1, which were quantified by histology after 7 days post-ischaemia. However, substantial neuronal damage was only seen when the time of flattening was more than 12 min and outlasted the time of ischaemia. The impairment of synaptic function, measured as the decrease of fEPSP slope 2 days post-ischaemia correlated with the later maturated structural damage in CA1. The fEPSP remained decreased until day 7 post-ischaemia. Animals with no damage (sham condition) showed a transient decrease of the fEPSP slope. In conclusion, our data show that the duration of EEG-flattening predicts the extent of neuronal damage. However, EEG-flattening just during the period of clamping both common carotid arteries—albeit an essential precondition for substantial CA1 cell loss to occur—is not sufficient to predict damage. The degree of impairment of evoked synaptic function of CA1 neurons (fEPSP) 2 days after ischaemia predicts the final extent of damage with significant probability. [ABSTRACT FROM AUTHOR]

The potential neuroprotection of nicotinamide on the consequences of perinatal asphyxia was investigated with triple organotypic cultures. Perinatal asphyxia was induced in vivo by immersing foetuses-containing uterine horns removed from ready-to-deliver rats into a water bath for 20 min. Sibling caesarean-delivered pups were used as controls. Three days later tissue from substantia nigra, neostriatum and neocortex was dissected and placed on a coverslip. After a month, the cultures were processed for immunocytochemistry and phenotyped with markers against the NMDA receptor subunit NR1, tyrosine hydroxylase (TH), or neuronal nitric oxide synthase (nNOS). Some cultures were analysed for cell viability. Nicotinamide (0.8 mmol/kg, i.p.) or saline was administered to asphyxia-exposed and caesarean-delivered control pups 24, 48 and 72 h after birth. Perinatal asphyxia produced a decrease of cell viability in substantia nigra, but not in neostriatum or neocortex. Immunocytochemistry confirmed the vulnerability of the substantia nigra, demonstrating that there was a significant decrease in the number of NR1 and TH-positive (+) cells/mm2, as well as a decrease in the length of TH+ processes, suggesting neurite atrophy. In control cultures, many nNOS+ cells were seen, with different features, regional distribution and cell body sizes. Following perinatal asphyxia, there was an increase in the number of nNOS+ cells/mm2 in substantia nigra, versus a decrease in neostriatum including reduced neurite length, and no apparent changes in neocortex. The main effect of nicotinamide was seen in the neostriatum, preventing the asphyxia-induced decrease in the number of nNOS+ cells and neurite length. Nicotinamide also prevented the effect of perinatal asphyxia on TH-positive neurite length. The present results support the idea that nicotinamide can prevent the effects produced by a sustained energy-failure condition, as occurring during perinatal asphyxia. [ABSTRACT FROM AUTHOR]

The aggregation of beta-amyloid to plaques in the brain is one of the hallmarks of Alzheimer disease (AD). Numerous studies have tried to elucidate to what degree amyloid peptides play a role in the neurodegenerative developments seen in AD. While most studies report an effect of amyloid on neural activity and cognitive abilities of rodents, there have been many inconsistencies in the results. This study investigated to what degree the different genetic backgrounds affect the outcome of beta-amyloid fragment (25–35) on synaptic plasticity in vivo in the rat hippocampus. Two strains, Wistar and Lister hooded rats, were tested. In addition, the effects of a strong (600 stimuli) and a weak stimulation protocol (100 stimuli) on impairments of LTP were analysed. Furthermore, since the state of amyloid aggregation appears to play a role in the induction of toxic processes, it was tested by dual polarisation interferometry to what degree and at what speed beta-amyloid (25–35) can aggregate in vitro. It was found that 100 nmol beta-amyloid (25–35) injected icv did impair LTP in Wistar rats when using the weak but not the strong stimulation protocol ( P < 0.001). One-hundred nano mole of the reverse sequence amyloid (35–25) had no effect. LTP in Lister Hooded rats was not impaired by amyloid at any stimulation protocol. The aggregation studies showed that amyloid (25–35) aggregated within hours, while amyloid (35–25) did not. These results show that the genetic background and the stimulation protocol are important variables that greatly influence the experimental outcome. The fact that amyloid (25–35) aggregated quickly and showed neurophysiological effects, while amyloid (35–25) did not aggregate and did not show any effects indicates that the state of aggregation plays an important role in the physiological effects. [ABSTRACT FROM AUTHOR]

We studied Fos expression in the central nociceptive pathways at different sedative levels in order to clarify the central mechanism of propofol’s nociceptive action. Sprague–Dawley rats received propofol (PRO) or pentobarbital (PEN) and were divided into two groups with different doses of drug administration (light and deep sedative levels) based on the electroencephalogram analysis. Rats at each sedative level received heat stimulation to their face and Fos immunohistochemistry was performed at various brain sites. We also infused lidocaine into the jugular vein to test whether PRO directly activated nociceptors distributed in the vein. Fos expression in two major ascending pain pathways (lateral and medial systems) and descending modulatory system were precisely analyzed following intravenous (i.v.) administration of PRO or PEN. Many Fos protein-like immunoreactive (Fos protein-LI) cells were expressed in the trigeminal spinal nucleus caudalis (Vc), parabrachial nucleus, parafascicular nucleus, a wide area of the primary somatosensory cortex, anterior cingulate cortex, amygdala, periaqueductal gray, solitary tract nucleus, and lateral hypothalamus following heating of the face during PRO or PEN infusion. The number of Fos protein-LI cells was significantly greater in many Central nervous system regions during PRO infusion compared with PEN. Fos expression was significantly greater in the Vc and Periaqueductal gray following greater amount of PRO infusions compared, whereas they were significantly smaller in the Vc in the rats with PEN infusion. The Fos expression was significantly depressed following i.v. infusion of lidocaine before PRO administration. The present findings suggest that PRO is involved in the enhancement of Vc activity through direct activation of the primary afferent fibers innervating veins, resulting in pain induction during infusion. [ABSTRACT FROM AUTHOR]

The present study shows that nicotinamide prevents the long-term effect of perinatal asphyxia on dopamine release monitored with in vivo microdialysis in the neostriatum of 3-month-old rats. Perinatal asphyxia was induced by immersing foetuses-containing uterine horns removed from ready-to-deliver rats into a water bath for 16 or 20 min. Sibling, spontaneous, and caesarean-delivered pups were used as controls. Saline or nicotinamide (0.8 mmol/kg, i.p.) was administered to control and asphyxia-exposed animals 24, 48, and 72 h after birth. After weaning, the rats were randomly distributed in laboratory cages for animal care under standard ad libitum laboratory conditions. Approximately 3 months after birth, control and asphyxia-exposed animals were implanted with microdialysis probes into the lateral neostriatum for measuring extracellular monoamine and metabolite levels with HPLC-coupled to an electrochemical detection system under basal, D-amphetamine, and K+-depolarising conditions. There was an asphyxia-dependent decrease of extracellular dopamine levels, mainly observed during the periods when D-amphetamine (100 μM) or KCl (100 mM) was added into the perfusion medium. Compared to that observed in caesarean-delivered controls, the effect of D-amphetamine on dopamine levels was decreased by approximately 30 and 70% in animals exposed to 16 and 20 min of perinatal asphyxia, respectively. The effect of K+-depolarisation was decreased by 45 and 83% in animals exposed to the same periods of asphyxia, respectively. Both effects were prevented by nicotinamide, even if the treatment started 24 h after the insult. The present results support the idea of nicotinamide as an interesting molecule, useful for protecting against anoxia/ischemia occurring at neonatal stages. Nicotinamide can help to restore NADH/NAD+ depletion, but also to inhibit PARP-1 overactivation, a mechanism of action that has attracted attention, representing a novel target for neuroprotection following insults involving energy failure. [ABSTRACT FROM AUTHOR]

We have investigated the effect of the Y2 receptor agonist (Y2 agonist; N- acetyl [Leu28,31] NPY 24-36), on contractions evoked by transmural electrical stimulation of sympathetic nerves of isolated arteries from a range of vascular beds in rats and guinea pigs. Contractions evoked by transmural stimulation of the rat renal, mesenteric and femoral arteries were significantly attenuated in the presence of the Y2 agonist. In these arteries, contractions were significantly inhibited in the presence of an α-adrenoceptor antagonist (76–97%). So we conclude that these responses were primarily mediated by noradrenaline and that the Y2 agonist attenuates the release of noradrenaline via presynaptic Y2 receptors. Contractions of the rat carotid artery were not attenuated by the Y2 agonist but were completely abolished in the presence of an α-adrenoceptor antagonist suggesting that in this artery the Y2 agonist has no effect on release of noradrenaline. In the guinea pig, carotid arteries contractions evoked by transmural nerve stimulation were attenuated in the presence of the Y2 agonist and inhibited by an α-adrenoceptor antagonist 75–87% suggesting that the Y2 agonist attenuates the release of noradrenaline via presynaptic Y2 receptors in this vessel. In the guinea pig femoral artery contractions evoked by transmural stimulation were not modified in the presence of the Y2 agonist but were completely abolished in the presence of an α-adrenoceptor antagonist. This suggests that the Y2 agonist does not modify noradrenaline release in this vessel. Contractions of the guinea pig mesenteric artery were significantly potentiated by the Y2 agonist, possibly by potentiation of neuropeptide Y (NPY) at the Y1 receptor. The Y1 antagonist inhibited more than 70 % of the response, indicating that the majority of the contraction was mediated by NPY. The current study demonstrates heterogeneity of neurotransmitter substances in sympathetic nerves supplying vascular beds within and across species and in subsequent functional response. [ABSTRACT FROM AUTHOR]

Peripheral sensory-motor neuropathy is one of the most frequent side effects of vincristine (VCR) administration, which often limits its usefulness in the treatment of a wide range of neoplastic diseases. The purpose of this work is to study VCR neurotoxicity in experimental animals from clinical, electrophysiological, and histological points of view. Sixty-five rats were used as a control group and 31 rats were divided into two groups and given VCR in two different regimens: the fixed-dose group (0.2 mg/kg) and the increasing-dose group (0.1 mg/kg, by an increment of 0.05 mg/kg/week). VCR was given intraperitoneally once weekly for five consecutive weeks. Electrophysiological examinations of the control and both treated groups were performed and included measurements of nerve conduction velocity and action potential (AP) amplitude of sciatic and tail nerves weekly during the period of treatment and 14 weeks after discontinuation of treatment. Histological sections of sciatic nerves were examined after the appearance of early electrophysiological changes, at the end of the 5th, and 19th weeks of the study (14 weeks after discontinuation of treatment). With the progress of the treatment, an increasing number of rats showing signs of neurological deficits were observed. During the first 5 weeks of this study, electrophysiological testing showed a nonsignificant difference in the conduction velocities of sciatic and tail nerves between the control and the treated groups, whereas a significant decrease in the amplitude of the sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) of the tested nerves was recorded. The reduction in the AP amplitude was associated with histological changes characterized by axonal degeneration with relative demyelination. Fourteen weeks after discontinuation of treatment, a significant increment in the SNAP and CMAP amplitudes of both sciatic and tail nerves was noticed. While the CMAP amplitude of the distal segment of the tail showed nonsignificant increment, lesser number of fibers with axonal and/or myelin lesions were found. The clinical, electrophysiological, and histological results suggest that VCR induces peripheral sensorimotor neuropathy of axonal type more prominent in the fixed- than the increasing-dose group. The discontinuation of VCR permitted the improvement of the electrophysiological and histological changes. The rat can be used as an animal model for studying VCR neurotoxicity. However, further studies on larger number of animals are required to evaluate the type of nerve fiber involvement and the site of damage. [ABSTRACT FROM AUTHOR]

Rats tactually explore a nearly spherical space field around their heads with their whiskers. The information sampled by the two sets of whiskers is integrated bilaterally at the cortical level in an activity dependent manner via the corpus callosum. We have recently shown that sensory activity in one barrel field cortex (BFC) modulates the processing of incoming sensory information to the other BFC. Whether interhemispheric integration is dynamically linked with corticothalamic modulation of incoming sensory activity is an important hypothesis to test, since subcortical relay neurons are directly modulated by cortical neurons through top-down processes. In the present study, we compared the direct sensory responses of single thalamic relay neurons under urethane anesthesia before and after inactivating the BFC contralateral to a thalamic neuron. The data show that silencing one BFC reduces response magnitude in contralateral thalamic relay neurons, significantly and reversibly, in response to test stimuli applied to the principal whisker at two times response threshold (2T) intensity for each unit. Neurons in the ventral posterior medial (VPM) nucleus and the medial division of the posterior nucleus (POm) react in a similar manner, although POm neurons are more profoundly depressed by inactivation of the contralateral BFC than VPM neurons. The results support the novel idea that the subcortical relay of sensory information to one hemisphere is strongly modulated by activity levels in the contralateral as well as in the ipsilateral SI cortex. The mechanism of the modulation appears to be based on shifting the stimulus–response curves of thalamic neurons, thereby rendering them more or less sensitive to sensory stimuli. We conclude that global sensory processing is created by combining activity in each cerebral hemisphere and continually balancing the flow of information to cortex by adjusting the responsiveness of ascending sensory pathways. [ABSTRACT FROM AUTHOR]

In response to a lesion, intact regions of cortex in both hemispheres undergo adaptive changes in network function. For example, changes in excitability and intracortical inhibition in primary motor cortex (M1) were reported after lesioning contralateral or ipsilateral brain regions. Close interactions exist between M1 and primary somatosensory cortex (S1) within one hemisphere. Therefore, we hypothesized that lasting modifications would occur in S1 excitability after lesioning ipsilateral M1. Imaging of intrinsic optical signals (IOS, at 570 nm) was used to investigate the evolution of the somatosensory cortical response evoked by contralateral median nerve stimulation during the first hour after a photothrombotic lesion to M1 (caudal motor cortex) of the rat ( n=10). Control rats ( n=6) received no lesion. Perfusion was monitored by Laser speckle imaging and the extent of the resulting lesion was determined histologically. Control animals did not show evidence for reduced perfusion, infarction, or changes in IOS. M1 infarction led to a significant increase in evoked response amplitude, duration, and area of activation, and a shortening of latencies. These parameters reached a plateau around 50 min after ischemia. These results indicate S1 hyperexcitability after M1 injury. Whether these adaptations contribute to functional deficits or play a role in recovery, remains to be determined. [ABSTRACT FROM AUTHOR]

Brailowsky and Garcia (1999) proposed the existence of a relationship between epilepsy and addiction. To prove this hypothesis, pentylenetetrazol kindled rats were tested in the conditioned place preference (CPP) paradigm for their reaction to various addictive drugs with different modes of action (morphine, cocaine and ethanol). In separate experiments, locomotor activity and body temperature after application of the same drugs were tested in kindled and non-kindled rats. In the CPP experiment there were significant differences between both groups of rats. Non-kindled animals showed place preference to morphine (5.0 mg/kg) or cocaine (20.0 mg/kg). This reaction was abolished in the kindled rats. Moreover, control rats demonstrated aversion to 2.0 g/kg ethanol. However, ethanol aversion was not detectable in kindled rats. Moreover, there was no difference between non-kindled and kindled rats in locomotor activity and body temperature after morphine (1.0 and 5.0 mg/kg), cocaine (10.0 and 20.0 mg/kg), or ethanol (0.5 and 2.0 g/kg) application. This suggests alterations in reward systems as a consequence of kindling. It is hypothesised that GABAergic neurones in the ventral tegmental area might play a major role in the alterations found. [ABSTRACT FROM AUTHOR]

Hyperglycemia aggravates ischemic brain injury, possibly due to the activation of signaling pathways involving reactive oxygen species, Src and mitogen-activated protein kinases. The aim of this study was to investigate the effects of the spin trap agent α-phenyl- N- tert-butyl nitrone (PBN), the Src family kinase inhibitor PP2 and the MEK1-inhibitor U0126 on focal hyperglycemic ischemic brain injury. Temporary middle cerebral artery occlusion (90 min) was induced in four groups of rats (PBN, PP2, and U0126 vs. control). Neurological testing and tetrazolium red staining were performed after 1 day. PBN decreased the infarct volume by 70% compared with the control ( P<0.05) and a tendency towards reduced infarcts was seen in the PP2 or U0126 groups. Furthermore, neurological testing was consistent with the volumetric analysis. In conclusion, PBN appears to be a potential neuroprotective agent in hyperglycemic, focal ischemic brain injury, while the efficacy of PP2 and U0126 could not be confirmed by the present data. [ABSTRACT FROM AUTHOR]

The mammalian auditory system evolved to extract meaningful information from complex acoustic environments. Spectrotemporal selectivity of auditory neurons provides a potential mechanism to represent natural sounds. Experience-dependent plasticity mechanisms can remodel the spectrotemporal selectivity of neurons in primary auditory cortex (A1). Electrical stimulation of the cholinergic nucleus basalis (NB) enables plasticity in A1 that parallels natural learning and is specific to acoustic features associated with NB activity. In this study, we used NB stimulation to explore how cortical networks reorganize after experience with frequency-modulated (FM) sweeps, and how background stimuli contribute to spectrotemporal plasticity in rat auditory cortex. Pairing an 8-4 kHz FM sweep with NB stimulation 300 times per day for 20 days decreased tone thresholds, frequency selectivity, and response latency of A1 neurons in the region of the tonotopic map activated by the sound. In an attempt to modify neuronal response properties across all of A1 the same NB activation was paired in a second group of rats with five downward FM sweeps, each spanning a different octave. No changes in FM selectivity or receptive field (RF) structure were observed when the neural activation was distributed across the cortical surface. However, the addition of unpaired background sweeps of different rates or direction was sufficient to alter RF characteristics across the tonotopic map in a third group of rats. These results extend earlier observations that cortical neurons can develop stimulus specific plasticity and indicate that background conditions can strongly influence cortical plasticity [ABSTRACT FROM AUTHOR]

Local injection of substance P (SP)-saporin can cause selective ablation of striatal interneurons expressing SP receptors (SPR). In this study, we evaluated quantitatively the impairment of skilled forelimb use after unilateral ablation of the striatal interneurons using a pasta matrix reaching task in rats. We found a significant decrease of the number of the pasta pieces (uncooked spaghetti) retrieved using the paw of the experimental side contralateral to the ablation, whereas the number of the pasta pieces retrieved using the paw of the intact side increased significantly. These findings, with our previous reports, suggest that the modulation of the cortico-striato-entopeduncular direct pathway by striatal interneurons is important for maintaining normal basal-ganglia control for skilled forelimb movements. [ABSTRACT FROM AUTHOR]

In the present study we used computer-controlled mechanical displacement of paired whiskers in normal and C-fiber-depleted rats to quantitatively examine the role of C-fibers in the receptive field properties of barrel cortical cells. In rodents when adjacent whiskers are stimulated prior to the main whisker responses to the main whisker are inhibited, the degree of inhibition being a function of the inter-deflection intervals. The adjacent-whisker-evoked inhibition of barrel cells in normal and C-fiber-depleted rats using neonatal capsaicin treatment were examined by stimulation of the adjacent whisker zero, 10, 20, 30, 50 and 100 ms prior to the main whisker deflection. C-fiber depletion reduced the suppressive effect of paired whisker stimulation at all of the tested inter-stimulus intervals without changing response latencies. The main effect was observed during the later phase of response (about 13-17 ms from stimulus onset) and not during the initial responses (7-12 ms). These results suggest that the inhibitory receptive field properties of low-threshold mechanical somatosensory cells are influenced by C-fibers. [ABSTRACT FROM AUTHOR]