Acquisition of morphine conditioned place preference increases the dendritic complexity of nucleus accumbens core neurons.

Contexts associated with opioid reward trigger craving and relapse in opioid addiction. Effects of reward-context associative learning on nucleus accumbens (NAc) dendritic morphology were studied using morphine conditioned place preference (CPP). Morphine-conditioned mice received saline and morphine 10 mg/kg subcutaneous (s.c.) on alternate days. Saline-conditioned mice received saline s.c. each day. Morphine-conditioned and saline-conditioned groups received injections immediately before each of eight daily conditioning sessions. Morphine homecage controls had no CPP training, but received saline and morphine in the homecage concomitantly with the morphine-conditioned group. Morphine conditioning produced greater place preference than saline conditioning. Mice were sacrificed 1 day after CPP expression. Dendritic changes were studied using Golgi-Cox staining and digital tracing of NAc core and shell neurons. In the NAc core, morphine homecage administration increased spine density, while morphine conditioning increased dendritic complexity, as defined by increased dendritic count, length and intersections. Place preference positively correlated with dendritic length and intersections in the NAc core. The core may mediate reward consolidation and determine how context-related signals from the shell lead to motor behavior. The combination of drug and conditioning in the morphine-conditioned group produced unique morphological effects different from the effects of drug or conditioning procedures by themselves. An additional study found no differences in neuron morphology between saline-conditioned mice, trained as described earlier, and mice that were not conditioned, but received saline in the homecage. The unique effect of morphine reward learning on NAc core dendrites reflects a brain substrate that could be targeted for therapeutic intervention in addiction.

Disturbances in fear extinction learning after mild traumatic brain injury in mice are accompanied by alterations in dendritic plasticity in the medial prefrontal cortex and basolateral nucleus of the amygdala.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have emerged as the signature injuries of the U.S. veterans who served in Iraq and Afghanistan, and frequently co-occur in both military and civilian populations. To better understand how fear learning and underlying neural systems might be altered after mTBI, we examined the acquisition of cued fear conditioning and its extinction along with brain morphology and dendritic plasticity in a mouse model of mTBI. To induce mTBI in adult male C57BL/6J mice, a lateral fluid percussive injury (LFP 1.7) was produced using a fluid pulse of 1.7 atmosphere force to the right parietal lobe. Behavior in LFP 1.7 mice was compared to behavior in mice from two separate control groups: mice subjected to craniotomy without LFP injury (Sham) and mice that did not undergo surgery (Unoperated). Following behavioral testing, neural endpoints (dendritic structural plasticity and neuronal volume) were assessed in the basolateral nucleus of the amygdala (BLA), which plays a critical sensory role in fear learning, and medial prefrontal cortex (mPFC), responsible for executive functions and inhibition of fear behaviors. No gross motor abnormalities or increased anxiety-like behaviors were observed in LFP or Sham mice after surgery compared to Unoperated mice. We found that all mice acquired fear behavior, assessed as conditioned freezing to auditory cue in a single session of 6 trials, and acquisition was similar across treatment groups. Using a linear mixed effects analysis, we showed that fear behavior decreased overall over 6 days of extinction training with no effect of treatment group across extinction days. However, a significant interaction was demonstrated between the treatment groups during within-session freezing behavior (5 trials per day) during extinction training. Specifically, freezing behavior increased across within-session extinction trials in LFP 1.7 mice, whereas freezing behavior in control groups did not change on extinction test days, reflecting a dissociation between within-trial and between-trial fear extinction. Additionally, LFP mice demonstrated bilateral increases in dendritic spine density in the BLA and decreases in dendritic complexity in the PFC. The translational implications are that individuals with TBI undergoing fear extinction therapy may demonstrate within-session aberrant learning that could be targeted for more effective treatment interventions.

Heightened muscle tension and diurnal hyper-vigilance following exposure to a social defeat-conditioned odor cue in rats.

Patients with post-traumatic stress disorder (PTSD) exhibit exaggerated daytime muscle tension as well as nocturnal sleep disturbances. Yet, these physiological and behavioral features of the disorder are little studied in animal models of PTSD. Accordingly, the present studies were designed to assess alterations in muscle tension and diurnal hyper-vigilance resulting from exposure to a social defeat stressor paired with an olfactory stimulus, which was then used as a reminder of stressor exposure. In the first series of experiments, rats presented with an olfactory cue paired previously with a single social defeat exhibited a significant increase in muscle tension 4 weeks following defeat. In the second series of experiments, an olfactory cue paired previously with a single social defeat induced a significant increase in locomotor activity among quiescent rats 4 weeks following stressor exposure. The present results thus support the a priori hypotheses that novel physiological and behavioral hallmarks of PTSD can be documented in an animal model of the disorder and that the present overt signs of reactive hyper-vigilance can be triggered by reintroduction of an olfactory stimulus present at the time of initial trauma exposure.

Improvement in motor and exploratory behavior in Rett syndrome mice with restricted ketogenic and standard diets.

Rett syndrome (RTT) is a rare X-linked autistic-spectrum neurological disorder associated with impaired energy metabolism, seizure susceptibility, progressive social behavioral regression, and motor impairment primarily in young girls. The objective of this study was to examine the influence of restricted diets, including a ketogenic diet (KD) and a standard rodent chow diet (SD), on behavior in male Mecp2(308/y) mice, a model of RTT. The KD is a high-fat, low-carbohydrate diet that has anticonvulsant efficacy in children with intractable epilepsy and may be therapeutic in children with RTT. Following an 11-day pretrial period, adult wild-type and mutant Rett mice were separated into groups that were fed either an SD in unrestricted or restricted amounts or a ketogenic diet (KetoCal) in restricted amounts for a total of 30 days. The restricted diets were administered to reduce mouse body weight by 20-23% compared to the body weight of each mouse before the initiation of the diet. All mice were subjected to a battery of behavioral tests to determine the influence of the diet on the RTT phenotype. We found that performance in tests of motor behavior and anxiety was significantly worse in male RTT mice compared to wild-type mice and that restriction of either the KD or the SD improved motor behavior and reduced anxiety. We conclude that although both restricted diets increased the tendency of Rett mice to explore a novel environment, the beneficial effects of the KD were due more to calorie restriction than to the composition of the diet. Our findings suggest that calorically restricted diets could be effective in reducing the anxiety and in improving motor behavior in girls with RTT.

Teratogenic effects of maternal antidepressant exposure on neural substrates of drug-seeking behavior in offspring.

If neurotransmitter balance is upset in the developing nervous system by exposure to antidepressant drugs, structural and functional hedonic phenotypes of offspring may be affected. In order to test this hypothesis, two groups of pregnant Wistar dams were exposed to vehicle or fluoxetine by implantation on gestational day 14 of osmotic minipumps delivering 0 or 10 mg/kg/day fluoxetine for 14 days. The consequences of perinatal fluoxetine exposure on offspring conflict-exploratory behavior were quantified using the elevated plus-maze on postnatal day (PND) 30. Beginning on PND 60, the reinforcing properties of acutely administered cocaine were examined using a place conditioning procedure. Beginning on PND 90, a subset of rats were implanted with jugular catheters and allowed to acquire self-administration of cocaine in an operant environment. In support of the hedonic modulation hypothesis, perinatal fluoxetine produced a significant decline in both nucleus accumbens cell count (-9%) and serotonin transporter-like immunoreactivity in the raphe nucleus (-35%) on PND 120. In the elevated plus-maze, perinatal fluoxetine exposure decreased (-21%) overall activity. In the place conditioning trial, only the fluoxetine-treated group exhibited a significant place preference for the compartment paired previously with cocaine. In a cocaine self-administration extinction trial, there was a statistically significant increase (350%) in extinction response rate among fluoxetine-exposed offspring. These findings suggest that perinatal exposure to fluoxetine perturbs adult serotonergic neurotransmission and produces a positive hedonic shift for conditioned reinforcing effects of cocaine.

Pathophysiological Bases of Comorbidity: Traumatic Brain Injury and Post-Traumatic Stress Disorder.

The high rates of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) diagnoses encountered in recent years by the United States Veterans Affairs Healthcare System have increased public awareness and research investigation into these conditions. In this review, we analyze the neural mechanisms underlying the TBI/PTSD comorbidity. TBI and PTSD present with common neuropsychiatric symptoms including anxiety, irritability, insomnia, personality changes, and memory problems, and this overlap complicates diagnostic differentiation. Interestingly, both TBI and PTSD can be produced by overlapping pathophysiological changes that disrupt neural connections termed the "connectome." The neural disruptions shared by PTSD and TBI and the comorbid condition include asymmetrical white matter tract abnormalities and gray matter changes in the basolateral amygdala, hippocampus, and prefrontal cortex. These neural circuitry dysfunctions result in behavioral changes that include executive function and memory impairments, fear retention, fear extinction deficiencies, and other disturbances. Pathophysiological etiologies can be identified using experimental models of TBI, such as fluid percussion or blast injuries, and for PTSD, using models of fear conditioning, retention, and extinction. In both TBI and PTSD, there are discernible signs of neuroinflammation, excitotoxicity, and oxidative damage. These disturbances produce neuronal death and degeneration, axonal injury, and dendritic spine dysregulation and changes in neuronal morphology. In laboratory studies, various forms of pharmacological or psychological treatments are capable of reversing these detrimental processes and promoting axonal repair, dendritic remodeling, and neurocircuitry reorganization, resulting in behavioral and cognitive functional enhancements. Based on these mechanisms, novel neurorestorative therapeutics using anti-inflammatory, antioxidant, and anticonvulsant agents may promote better outcomes for comorbid TBI and PTSD.

Neural, endocrine and electroencephalographic hyperreactivity to human contact: a diathesis-stress model of seizure susceptibility in El mice.

The El mouse strain provides a non-induced model of idiopathic, multifactorial epilepsy in which seizures are elicited in response to stressful environmental stimuli such as tail suspension handling. In the present studies, genetically seizure susceptible El and non-susceptible ddY control mice were exposed to tail suspension, foot-shock and social stressors in order to test the hypothesis that neural and physiological responses to such stimuli would be exaggerated in the El strain. The first experiment assessed neural cell density, stress neuropeptide (corticotropin releasing factor--CRF) levels, and plasma corticosterone activation in El and ddY mice in an unhandled control condition or following exposure to tail suspension or foot-shock stressors. The second experiment assessed brain electroencephalographic activity using telemetrically monitored skull surface electrodes in El and ddY mice exposed to tail suspension or social interaction stressors. Assessment of El mouse brains revealed higher cell counts in amygdala and elevated CRF peptide content in the paraventricular thalamic nucleus relative to ddY controls. El mice exhibited significantly elevated plasma corticosterone levels 60 min following exposure to tail suspension and foot-shock stressors relative to ddY controls. Finally, El mice exhibited significantly elevated brain electroencephalographic (1-4 Hz) activity in response to tail suspension, but not social interaction, relative to ddY controls. These results indicate that potentiated neural, endocrine and physiological activation arises in the El strain following exposure to a known seizure trigger stimulus, involuntary tail suspension handling. The findings support a diathesis-stress hypothesis in which genetically seizure susceptible El mice exhibit a multifaceted hyperreactivity to noxious environmental stimuli.

Seizure prophylaxis in an animal model of epilepsy by dietary fluoxetine supplementation.

Clinical and animal model evidence suggests that selective serotonin reuptake inhibitors (SSRIs) act as anticonvulsants. The present studies tested the possibility that the El mouse model of genetically predisposed/handling-triggered epilepsy would exhibit fewer seizures following SSRI treatment via dietary fluoxetine adulteration. In particular, potential bioenergetic and neural mechanisms for anticonvulsant efficacy of fluoxetine were explored using food intake/body weight monitoring and quantification of brain serotonin transporter protein. El mice consuming a chow diet ad libitum or yoked in quantity to fluoxetine diet intake exhibited seizure incidence of 40% in response to tail-suspension handling, whereas seizures were abolished (0%) among El mice consuming a fluoxetine-adultered diet over 7 days. A 3 day period of fluoxetine administration was insufficient to exert anticonvulsant efficacy and all treatment groups exhibited the same circadian locomotor activity patterns at the time of seizure susceptibility testing. Bioenergetic factors could not account for the anticonvulsant efficacy of fluoxetine since yoked diet controls with matched food intake, body weight change and blood glucose levels exhibited the same 40% seizure incidence as ad libitum chow controls. Importantly, the 7 day period of dietary fluoxetine exposure was effective in selectively reducing cell density in the parietal cortex and increasing serotonin transporter protein content in the nucleus accumbens. Taken together, these results suggest that dietary fluoxetine supplementation abolishes handling-induced seizure susceptibility in El mice via a neural remodeling mechanism independent of energy balance.

Antisocial and seizure susceptibility phenotypes in an animal model of epilepsy are normalized by impairment of brain corticotropin-releasing factor.

Social interaction phenotyping is an unexplored niche in animal modeling of epilepsy despite the sensitivity of affiliative behaviors to emotionality and stress, which are known seizure triggers. Thus, the present studies examined the social phenotype of seizure-susceptible El and nonsusceptible ddY strains both in untreated animals and following preexposure to a handling stressor. The second aim of the present studies was to evaluate the dependence of sociability in El mice on the proconvulsive, stress neuropeptide corticotropin-releasing factor (CRF) using CRF-SAP, a conjugate of CRF and the toxin saporin, which selectively reduced CRF peptide levels in the basolateral amygdala of El mice. El mice exhibited lower social investigation times than ddY counterparts, whereas central administration of CRF-SAP normalized social investigation times relative to ddY controls. Moreover, handling-induced seizures in El mice were reduced by 50% following treatment with CRF-SAP relative to saporin alone-injected El controls. The results of this study suggest that tonically activated CRF systems in the El mouse brain suppress affiliative behavior and facilitate evoked seizures.

Short-term social recognition memory deficit and atypical social and physiological stressor reactivity in seizure-susceptible El mice.

The present studies characterize working memory capabilities in the El mouse model of epilepsy using a species-typical social recognition memory task. As the El mouse exhibits a stress hyper-reactivity phenotype, the impact of hypertonic saline consumption, a memory modulatory treatment, upon social recognition performance was also examined. The hypotheses under test were: (1) that seizure susceptible El mice would perform poorly in the short-term working memory task relative to seizure resistant ddY controls, and (2) that the behavioral and neural responses to stressor exposure would be atypical in El mice. Results revealed a short-term working memory deficit and altered reactivity to social, environmental, and physiological stressors in El mice. In Experiment 1, El mice exhibited poor sociability and decreased olfactory investigation times, both anxiogenic-like traits, compared to ddY controls. In Experiment 2, El mice exhibited poor working memory performance compared to capable performance in ddY controls. Social recognition memory in ddY mice was abolished, however, by salt-loading whereas El mice were unaffected by exposure to this physiological stressor. In Experiment 3, all salt-loaded mice exhibited enhanced brain stress neuropeptide (corticotropin releasing factor-CRF) content, and salt-loaded El mice exhibited a 70% reduction in handling-induced seizures. These findings suggest that El mice exhibit high emotionality as well as atypical reactions to stressor exposure, and that these characteristics impact social working memory performance and seizure susceptibility.

Dopamine D1 receptor agonist treatment attenuates extinction of morphine conditioned place preference while increasing dendritic complexity in the nucleus accumbens core.

The dopamine D1 receptor (D1R) has a role in opioid reward and conditioned place preference (CPP), but its role in CPP extinction is undetermined. We examined the effect of D1R agonist SKF81297 on the extinction of opioid CPP and associated dendritic morphology in the nucleus accumbens (NAc), a region involved with reward integration and its extinction. During the acquisition of morphine CPP, mice received morphine and saline on alternate days; injections were given immediately before each of eight daily conditioning sessions. Mice subsequently underwent six days of extinction training designed to diminish the previously learned association. Mice were treated with either 0.5mg/kg SKF81297, 0.8mg/kg SKF81297, or saline immediately after each extinction session. There was a dose-dependent effect, with the highest dose of SKF81297 attenuating extinction, as mice treated with this dose had significantly higher CPP scores than controls. Analysis of medium spiny neuron morphology revealed that in the NAc core, but not in the shell, dendritic arbors were significantly more complex in the morphine conditioned, SKF81297-treated mice compared to controls. In separate experiments using mice conditioned with only saline, SKF81297 administration after extinction sessions had no effect on CPP and produced differing effects on dendritic morphology. At the doses used in our experiments, SKF81297 appears to maintain previously learned opioid conditioned behavior, even in the face of new information. The D1R agonist's differential, rather than unidirectional, effects on dendritic morphology in the NAc core suggests that it may be involved in encoding reward information depending on previously learned behavior.

Brain penetrance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist.

The present studies were designed to evaluate the competitive binding properties and functional effects of a novel nonpeptide CRF1 receptor antagonist, R121919. R121919 administered in doses of 0.63 to 20 mg/kg p.o. 60 min pretest in Wistar rats dose dependently attenuated the swim stress-induced anxiogenic-like behavior in the elevated plus-maze model of anxiety. Moreover, receptor autoradiography revealed that R121919 dose-dependently occupied brain CRF1 receptors in subjects tested in the plus-maze experiment. Orally administered doses of up to 20 mg/kg R121919 also blunted basal and swim stress-induced pituitary-adrenocortical activation, produced additional anxiolytic-like behavioral actions in the defensive withdrawal and defensive burying paradigms, and functionally antagonized the locomotor stimulatory properties of exogenously administered CRF. Taken together, these results suggest that the anxiolytic-like efficacy of R121919 in attenuating the stress-, novelty-, shock-, and CRF-induced increases in behavioral arousal is correlated with competitive blockade of central CRF1 receptors.

Modulation of social learning in rats by brain corticotropin-releasing factor.

In order to investigate the impact of brain stress-related neuropeptide tone on learning and memory performance, juvenile recognition ability was examined in adult female rats using a social memory test following pharmacological inactivation and activation of corticotropin-releasing factor (CRF) systems. In particular, administration of a competitive CRF receptor antagonist [0.2, 1 or 5 microg intracerebroventricular doses of D-Phe CRF (12-41)], dose dependently impaired learning performance over a 30-min delay to 27% of vehicle controls values. In complementary fashion, forgetting produced by a 120-min delay that impaired social recognition performance to 29% of 30-min delay control levels was reversed by administration of a 1-microg dose of the CRF binding protein ligand inhibitor, r/h CRF (6-33), although a higher 5 microg dose exerted non-specific effects on social investigation. These findings suggest that brain CRF systems are physiologically relevant for social memory capacity in the absence of stressor exposure.

Nonexercise muscle tension and behavioral fidgeting are positively correlated with food availability/palatability and body weight in rats.

While certain measures of energy expenditure such as respiratory quotient and thermogenesis are readily quantifiable using existing animal models, the mechanism for and measurement of energy expenditure via nonexercise activity have not been thoroughly characterized. This low intensity form of physical exertion, associated with involuntary fidgeting and postural changes in man, was quantified in the present studies using passive measurement of muscle tension in rats. In particular, long-term weight loss and gain were induced using diet yoking and feeding of preferred foods in order to assess corresponding changes in locomotor activity and radiotelemetered measures of muscle tension, temperature and global activity. Hind limb muscle tension, but not body temperature, was increased 30-60% by enhancing the availability or palatability of food relative to the decreased muscle tension resulting from limited food availability. Enhancing food availability or palatability also produced a relative 5-15% increase in the amount of telemetered global activity. Importantly, neither diet yoking nor provision of a highly preferred diet altered a precise measure of behavioral locomotor activity. These results suggest that muscle tension and activity-in-place are positively correlated with weight change in the present studies and that these mechanisms of energy expenditure are mobilized by environmental changes in diet composition and meal pattern.

Extinction of opiate reward reduces dendritic arborization and c-Fos expression in the nucleus accumbens core.

Recurrent opiate use combined with environmental cues, in which the drug was administered, provokes cue-induced drug craving and conditioned drug reward. Drug abuse craving is frequently linked with stimuli from a prior drug-taking environment via classical conditioning and associative learning. We modeled the conditioned morphine reward process by using acquisition and extinction of conditioned place preference (CPP) in C57BL/6 mice. Mice were trained to associate a morphine injection with a drug context using a classical conditioning paradigm. In morphine conditioning (0, 0.25, 0.5, 1, 5, or 10 mg/kg) experimental mice acquired a morphine CPP dose response with 10mg/kg as most effective. During morphine CPP extinction experiments, mice were divided into three test groups: morphine CPP followed by extinction training, morphine CPP followed by sham extinction, and saline controls. Extinction of morphine CPP developed within one extinction experiment (4 days) that lasted over two more trials (another 8 days). However, the morphine CPP/sham extinction group retained a place preference that endured through all three extinction trials. Brains were harvested following CPP extinction and processed using Golgi-Cox impregnation. Changes in dendritic morphology and spine quantity were examined in the nucleus accumbens (NAc) Core and Shell neurons. In the NAcCore only, morphine CPP/extinguished mice produced less dendritic arborization, and a decrease in neuronal activity marker c-Fos compared to the morphine CPP/sham extinction group. Extinction of morphine CPP is associated with decreased structural complexity of dendrites in the NAcCore and may represent a substrate for learning induced structural plasticity relevant to addiction.

Repeated valproate treatment facilitates fear extinction under specific stimulus conditions.

Single dose treatment with histone deacetylase inhibitor (HDACi) agents has been shown to enhance extinction learning in rodent models under certain conditions. The present novel studies were designed to examine the effects of repeated HDACi treatment, with valproate or sodium butyrate, on the extinction of conditioned fear. In Experiments 1 and 2, short duration CS exposure (30s) in combination with vehicle administration progressively attenuated conditioned fear responses over 40 or more sessions. This effective extinction training was not augmented by HDACi treatments. In Experiment 3, we used a long duration CS exposure (120 s) to weaken extinction training. With these extinction parameters, repeated valproate treatment substantially facilitated the acquisition and retention of fear extinction. Results of this study extend previous work suggesting that HDACi's have utility in augmenting the efficiency of fear extinction, although their apparent benefits are critically dependent upon specific parameters of extinction training.

Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice.

Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70-80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls. During fear acquisition, freezing behavior was significantly affected by both shock exposure and trial number. For fear extinction, mice were exposed to the conditioned stimulus tone in the absence of shock administration and behavioral responses significantly varied by shock treatment. In the retention tests over 3 weeks, the percentage time spent freezing varied with the factor of extinction training. In all treatment groups, alterations in dendritic plasticity were analyzed using Golgi-Cox staining of dendrites in the BLA. Spine density differed between the fear conditioned group and both the fear extinction and control groups on third order dendrites. Spine density was significantly increased in the fear conditioned group compared to the fear extinction group and controls. Similarly in Sholl analyses, fear conditioning significantly increased BLA spine numbers and dendritic intersections while subsequent extinction training reversed these effects. In summary, fear extinction produced enduring behavioral plasticity that is associated with a reversal of alterations in BLA dendritic plasticity produced by fear conditioning. These neuroplasticity findings can inform our understanding of structural mechanisms underlying stress-related pathology can inform treatment research into these disorders.

Treatment of addiction and anxiety using extinction approaches: neural mechanisms and their treatment implications.

Clinical interventions which produce cue and contextual extinction learning can reduce craving and relapse in substance abuse and inhibit conditioned fear responses in anxiety disorders. In both types of disorders, classical conditioning links unconditioned drug or fear responses to associated contextual cues and result in enduring pathological responses to multiple stimuli. Extinction therapy countermeasures seek to reduce conditioned responses using a set of techniques in which patients are repeatedly exposed to conditioned appetitive or aversive stimuli using imaginal imagery, in vivo exposure, or written scripts. Such interventions allow patients to rehearse more adaptive responses to conditioned stimuli. The ultimate goal of these interventions, extinction of the original conditioned response, is a new learning process that results in a decrease in frequency or intensity of conditioned responses to drug or fear cues. This review explores extinction approaches in conditioned drug reward and fear responses. The behavioral, neuroanatomical and neurochemical mechanisms of conditioned reward and fear responses and their extinction are derived from our understanding of the animal literature. Extensive neuroscience research shows that even though many mechanisms differ in conditioned fear and reward, converging prefrontal cortical glutamatergic pathways underlie extinction learning. Efficacy of pharmacological and behavioral treatment approaches in addiction and anxiety disorders may be optimized by enhancing extinction and weakening the bond between the original conditioned stimuli and conditioned responses. Adjunctive pharmacotherapy approaches using agents which alter glutamate or γ-aminobutyric acid signaling or epigenetic mechanisms in prefrontal cortical pathways can enhance extinction learning. A comparative study of extinction processes and its neural mechanisms can be translated into more effective behavioral and pharmacological treatment approaches in substance abuse and anxiety.

Dietary omega-3 fatty acid supplementation for optimizing neuronal structure and function.

Direct actions of omega-3 polyunsaturated fatty acids (PUFAs) on neuronal composition, neurochemical signaling and cognitive function constitute a multidisciplinary rationale for classification of dietary lipids as "brain foods." The validity of this conclusion rests upon accumulated mechanistic evidence that omega-3 fatty acids actually regulate neurotransmission in the normal nervous system, principally by modulating membrane biophysical properties and presynaptic vesicular release of classical amino acid and amine neurotransmitters. The functional correlate of this hypothesis, that certain information processing and affective coping responses of the central nervous system are facilitated by bioavailability of omega-3 fatty acids, is tentatively supported by developmental and epidemiological evidence that dietary deficiency of omega-3 fatty acids results in diminished synaptic plasticity and impaired learning, memory and emotional coping performance later in life. The present review critically examines available evidence for the promotion in modern society of omega-3 fatty acids as adaptive neuromodulators capable of efficacy as dietary supplements and as potential prophylactic nutraceuticals for neurological and neuropsychiatric disorders.

Neurobehavioral consequences of stressor exposure in rodent models of epilepsy.

Both normal, non-epileptic as well as seizure-prone rodents exhibit a spectrum of anxiogenic-like behaviors in response to stressor exposure. Comparative analysis reveals that the same set of emotionality dependent measures is sensitive to both stress reactivity in normal rodents as well as stress hyperreactivity typically seen in seizure-prone rodents. A variety of unconditioned, exploratory tasks reflect global sensitivity to stressor exposure in the form of behavioral inhibition of locomotor output. Moreover, well chosen stressors can trigger de novo seizures with or without a history of seizure incidence. Seizures may be elicited in response to stressful environmental stimuli such as noxious noises, tail suspension handling, or home cage disturbance. Stress reactivity studies in rodents with a genetic predisposition to seizures have yielded important clues regarding brain substrates that mediate seizure ontogeny and modulate ictogenesis. Brains of seizure susceptible rodents reflect elevated content of the stress-related neuropeptide, corticotropin-releasing factor (CRF) in several nuclei relative to non-susceptible controls and neutralization of brain CRF attenuates seizure sensitivity. Findings outlined in this review support a diathesis-stress hypothesis in which behavioral- and neuro-pathologies of genetically seizure susceptible rodents arise in part due to multifaceted hyperreactivity to noxious environmental stimuli.