Pituitary adenylate cyclase-activating polypeptide (PACAP) in the paraventricular nucleus of the thalamus: Influence on binge-type eating in male and female mice.

Binge eating disorder, characterized by the overconsumption of food in a discrete time period, is the most common eating disorder in the United States, but its neurological basis is not fully understood. The paraventricular nucleus of the thalamus (PVT) is a limbic brain region implicated in eating, and the anorexigenic neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), is densely expressed in the PVT. This study sought to examine the possible involvement of PACAP in the PVT in binge-type eating. First, a model of binge-type eating was established in mice. Male and female C57BL/6J mice were given limited access to Milk Chocolate Ensure Plus® or had access only to chow and water. Under this model, while males and females both engaged in binge-type eating with Ensure, females engaged in this behavior to a greater degree than males. Next, the role of PACAP in the PVT was defined in relation to binge-type eating. Using quantitative real-time PCR, females were found to have higher baseline levels of PVT PACAP mRNA than males, but only males showed an increase in levels of PACAP after a history of binge-type eating, and only males showed a reduction in levels of PACAP immediately prior to a binge session. Using chemogenetics in PACAP-Cre transgenic mice on a C57BL/6J background, activation of PVT PACAP+ cells with a Cre-dependent Gq-DREADD was found to reduce binge-type eating, significantly in male but not female mice. These results indicate that PVT PACAP is involved in binge-type eating in a sex-dependent manner, with a decrease in PVT PACAP levels preceding binge-type eating in male mice, and enhanced PVT PACAP+ cell activity suppressing binge-type eating in male mice. Together, these results suggest that the PACAP system could be targeted in specific patient populations to help treat binge eating disorder.

Kappa-opioid receptor stimulation in the nucleus accumbens shell and ethanol drinking: Differential effects by rostro-caudal location and level of drinking.

Although the kappa-opioid receptor (KOR) and its endogenous ligand, dynorphin, are believed to be involved in ethanol drinking, evidence on the direction of their effects has been mixed. The nucleus accumbens (NAc) shell densely expresses KORs, but previous studies have not found KOR activation to influence ethanol drinking. Using microinjections into the NAc shell of male and female Long-Evans rats that drank under the intermittent-access procedure, we found that the KOR agonist, U50,488, had no effect on ethanol drinking when injected into the middle NAc shell, but that it promoted intake in males and high-drinking females in the caudal NAc shell and high-drinking females in the rostral shell, and decreased intake in males and low-drinking females in the rostral shell. Conversely, injection of the KOR antagonist, nor-binaltorphimine, stimulated ethanol drinking in low-drinking females when injected into the rostral NAc shell and decreased drinking in high-drinking females when injected into the caudal NAc shell. These effects of KOR activity were substance-specific, as U50,488 did not affect sucrose intake. Using quantitative real-time PCR, we found that baseline gene expression of the KOR was higher in the rostral compared to caudal NAc shell, but that this was upregulated in the rostral shell with a history of ethanol drinking. Our findings have important clinical implications, demonstrating that KOR stimulation in the NAc shell can affect ethanol drinking, but that this depends on NAc subregion, subject sex, and ethanol intake level, and suggesting that this may be due to differences in KOR expression.

Short-chain-fatty acid valerate reduces voluntary alcohol intake in male mice.

Background: Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. Development of novel therapeutic and preventative approaches is highly desirable. Accumulating evidence in the past several years has established associations between the gut microbiome and microbial metabolites with drinking behavior, but druggable targets and their underlying mechanism of action are understudied. Results: Here, using a drink-in-the-dark mouse model, we identified a microbiome metabolite-based novel treatment (sodium valerate) that can reduce excessive alcohol drinking. Sodium valerate is a sodium salt of valeric acidshort-chain-fatty-acid with similar structure as γ-aminobutyric acid (GABA). Ten days of oral sodium valerate supplementation attenuates excessive alcohol drinking by 40%, reduces blood ethanol concentration by 53%, and improves anxiety-like or approach-avoidance behavior in male mice, without affecting overall food and water intake. Mechanistically, sodium valerate supplementation increases GABA levels across stool, blood, and amygdala. It also significantly increases H4 acetylation in the amygdala of mice. Transcriptomics analysis of the amygdala revealed that sodium valerate supplementation led to changes in gene expression associated with functional pathways including potassium voltage-gated channels, inflammation, glutamate degradation, L-DOPA degradation, and psychological behaviors. 16S microbiome profiling showed that sodium valerate supplementation shifts the gut microbiome composition and decreases microbiome-derived neuroactive compounds through GABA degradation in the gut microbiome. Conclusion: Our findings suggest that the sodium valerate holds promise as an innovative therapeutic avenue for the reduction of habitual binge drinking, potentially through multifaceted mechanisms.

Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine.

The hypocretins/orexins (HCRT) have been demonstrated to influence motivation for cocaine through actions on dopamine (DA) transmission. Pharmacological or genetic disruption of the hypocretin receptor 1 (Hcrtr1) reduces cocaine self-administration, blocks reinstatement of cocaine seeking, and decreases conditioned place preference for cocaine. These effects are likely mediated through actions in the ventral tegmental area (VTA) and resulting alterations in DA transmission. For example, HCRT drives VTA DA neuron activity and enhances the effects of cocaine on DA transmission, while disrupting Hcrtr1 attenuates DA responses to cocaine. These findings have led to the perspective that HCRT exerts its effects through Hcrtr1 actions in VTA DA neurons. However, this assumption is complicated by the observation that Hcrtr1 are present on both DA and GABA neurons in the VTA and HCRT drives the activity of both neuronal populations. To address this issue, we selectively knocked down Hcrtr1 on either DA or GABA neurons in the VTA and examined alterations in DA transmission and cocaine self-administration in female and male rats. We found that Hcrtr1 knockdown in DA neurons decreased DA responses to cocaine, increased days to acquire cocaine self-administration, and reduced motivation for cocaine. Although, Hcrtr1 knockdown in GABA neurons enhanced DA responses to cocaine, this manipulation did not affect cocaine self-administration. These observations indicate that while Hcrtr1 on DA versus GABA neurons exert opposing effects on DA transmission, only Hcrtr1 on DA neurons affected acquisition or motivation for cocaine - suggesting a complex interplay between DA transmission and behavior.

The functional heterogeneity of PACAP: Stress, learning, and pathology.

Pituitary adenylate cyclase-activating peptide (PACAP) is a highly conserved and widely expressed neuropeptide that has emerged as a key regulator of multiple neural and behavioral processes. PACAP systems, including the various PACAP receptor subtypes, have been implicated in neural circuits of learning and memory, stress, emotion, feeding, and pain. Dysregulation within these PACAP systems may play key roles in the etiology of pathological states associated with these circuits, and PACAP function has been implicated in stress-related psychopathology, feeding and metabolic disorders, and migraine. Accordingly, central PACAP systems may represent important therapeutic targets; however, substantial heterogeneity in PACAP systems related to the distribution of multiple PACAP isoforms across multiple brain regions, as well as multiple receptor subtypes with several isoforms, signaling pathways, and brain distributions, provides both challenges and opportunities for the development of new clinically-relevant strategies to target the PACAP system in health and disease. Here we review the heterogeneity of central PACAP systems, as well as the data implicating PACAP systems in clinically-relevant behavioral processes, with a particular focus on the considerable evidence implicating a role of PACAP in stress responding and learning and memory. We also review data suggesting that there are sex differences in PACAP function and its interactions with sex hormones. Finally, we discuss both the challenges and promise of harnessing the PACAP system in the development of new therapeutic avenues and highlight PACAP systems for their critical role in health and disease.

A critical review of effects on ethanol intake of the dynorphin/kappa opioid receptor system in the extended amygdala: From inhibition to stimulation.

The dynorphin (DYN)/kappa opioid receptor (KOR) system has increasingly been investigated as a possible pharmacotherapeutic target for alcohol use disorder, but findings on the direction of its effects have been mixed. Activation of KORs by DYN has been shown to elicit dysphoric effects, and the DYN/KOR system has canonically been considered particularly important in driving alcohol intake through negative reinforcement in dependent states. However, this review also highlights its activity in opposing the positive reinforcement that drives alcohol intake at earlier stages. Both DYN and KORs are concentrated in the extended amygdala, a set of interconnected regions that includes the bed nucleus of the stria terminalis, central nucleus of the amygdala, and nucleus accumbens shell. This review focuses on the role of the DYN/KOR system in the extended amygdala in ethanol use. It begins by examining the effects of ethanol on the expression of DYN/KOR in the extended amygdala, expression of DYN/KOR in alcohol-preferring and alcohol-avoiding animals, and the effects of knocking out DYN/KOR genes on ethanol intake. Then, it examines the effects on ethanol use in both dependent and nondependent states from systemic pharmacological manipulations of DYN/KOR and from specific manipulation of this system in regions of the extended amygdala. We propose that greater expression and binding of DYN/KOR, by reducing the positive reinforcement that drives early stages of intake, initially acts to prevent the escalation of ethanol drinking. However, prolonged, binge-like, or intermittent ethanol intake enhances levels of DYN/KOR in the extended amygdala such that the system ultimately facilitates the negative reinforcement that drives later stages of ethanol drinking. This review highlights the potential of the DYN/KOR system as a target that can affect different outcomes across different stages of ethanol drinking and the development of alcohol use disorder.

Sex-related differences in endogenous pituitary adenylate cyclase-activating polypeptide (PACAP) in the thalamic paraventricular nucleus: Implications for addiction neuroscience.

Males and females exhibit differences in motivated and affective behavior; however, the neural substrates underlying these differences remain poorly understood. In the paraventricular nucleus of the thalamus (PVT), sex-related differences in neuronal activity have been identified in response to motivated behavior tasks and affective challenges. Within the PVT, the neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), is highly expressed and is also involved in motivated and affective behavior. The purpose of this study was to compare the expression of PACAP mRNA and peptide in the PVT of males and females. Analysis with quantitative real-time PCR in mice revealed that females had significantly higher levels of PACAP mRNA than males in the whole PVT, but no differences in the neuropeptides enkephalin or corticotropin releasing factor (CRF) in this brain region. While in rats, females demonstrated a trend for greater gene expression than males in the anterior/middle and middle/posterior PVT, they again showed no differences in enkephalin or CRF. Analysis with immunofluorescent histochemistry revealed that female mice had significantly more PACAP-containing cells than males as a function of area throughout the PVT, and that female rats had significantly more PACAP-27 and PACAP-38-containing cells than males, both as a percentage of total cells and as a function of PVT area. For PACAP-27, this specifically occurred in the anterior PVT, and for PACAP-38, it occurred throughout the anterior, middle, and posterior PVT. These results suggest that sex-related differences in PVT PACAP may underly some of the established sex-related differences in motivated and affective behavior.

Inactivation of the thalamic paraventricular nucleus promotes place preference and sucrose seeking in male rats.

RATIONALE: The experience of reward entails both positive affect and motivation. While the brain regions responsible for these distinct aspects of reward are dissociable from each other, the paraventricular nucleus of the thalamus (PVT) may play a role in both. OBJECTIVES: To investigate the role of the PVT in both affect and motivation, and to identify neuropeptides that might mediate these effects. METHODS: Male rats were tested for conditioned place preference following temporary inactivation of the anterior or posterior PVT with local injections of the GABAB and GABAA agonists, baclofen + muscimol. They were tested for sucrose seeking under a fixed ratio 3 (FR3) schedule of reinforcement and after extinction, following injection into the posterior PVT of baclofen + muscimol or saline vehicle. Finally, quantitative real-time PCR was used to examine local neuropeptide gene expression following injection into the posterior PVT of baclofen + muscimol or saline vehicle. RESULTS: Conditioned place preference was induced by temporary inactivation of the posterior but not anterior PVT. While sucrose seeking under an FR3 schedule of reinforcement was unaffected by inactivation of the posterior PVT, reinstatement of sucrose seeking was promoted by posterior PVT inactivation. Local gene expression of pituitary adenylate cyclase-activating polypeptide (PACAP), but not enkephalin or neurotensin, was reduced following inactivation of the posterior PVT. CONCLUSIONS: Temporary inactivation of the posterior PVT affects both affect and motivation as well as local gene expression of PACAP. These results suggest that the posterior PVT is one brain region that may participate in both major aspects of reward.

Sex-related differences in pattern of ethanol drinking under the intermittent-access model and its impact on exploratory and anxiety-like behavior in Long-Evans rats.

BACKGROUND: While men in the United States consume more alcohol than women, rates of drinking are converging. Nevertheless, females remain underrepresented in preclinical alcohol research. Here, we examined rats' sex-related differences in patterns of ethanol (EtOH) drinking and the effects of this drinking on exploratory and anxiety-like behavior. METHODS: Adult male and female Long-Evans rats were given 20% ethanol under the intermittent-access two-bottle-choice paradigm. Their intake was measured daily for the first 7 weeks. During the eighth week, intake was measured over the 24 h of daily access. During the ninth week, they, along with EtOH-naive controls, were tested prior to daily access in a novel chamber, light-dark box, and hole board apparatus. During the tenth week, blood ethanol concentration (BEC) was assessed after 30 to 40 min of access. RESULTS: Females overall demonstrated higher ethanol intake and preference across all access weeks than males, although only half of females drank significantly more than males. Across 24 h of daily access, both sexes had their highest intake in the first 30 min and their lowest in the middle of the light phase of the light/dark cycle. Despite their greater ethanol intake, females did not show significantly different BECs than males. In behavioral tests, females showed less vertical time in a novel activity chamber, more movement between chambers in a light-dark box, and more nose pokes in a hole-board apparatus than males. While a history of ethanol drinking led to a trend for lower vertical time in the activity chamber and greater chamber entries in the light-dark box, the effects were not sex-dependent. CONCLUSIONS: These results suggest that female and male rats could both be tested for acute effects of ethanol after 30 min of daily access, but that nuanced considerations are needed in the design of these experiments and the interpretation of their findings.

Intranasal Administration of Oxytocin Attenuates Social Recognition Deficits and Increases Prefrontal Cortex Inhibitory Postsynaptic Currents following Traumatic Brain Injury.

Pediatric traumatic brain injury (TBI) results in heightened risk for social deficits that can emerge during adolescence and adulthood. A moderate TBI in male and female rats on postnatal day 11 (equivalent to children below the age of 4) resulted in impairments in social novelty recognition, defined as the preference for interacting with a novel rat compared with a familiar rat, but not sociability, defined as the preference for interacting with a rat compared with an object in the three-chamber test when tested at four weeks (adolescence) and eight weeks (adulthood) postinjury. The deficits in social recognition were not accompanied by deficits in novel object recognition memory and were associated with a decrease in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) recorded from pyramidal neurons within Layer II/III of the medial prefrontal cortex (mPFC). Whereas TBI did not affect the expression of oxytocin (OXT) or the OXT receptor (OXTR) mRNAs in the hypothalamus and mPFC, respectively, intranasal administration of OXT before behavioral testing was found to reduce impairments in social novelty recognition and increase IPSC frequency in the mPFC in brain-injured animals. These results suggest that TBI-induced deficits in social behavior may be linked to increased excitability of neurons in the mPFC and suggests that the regulation of GABAergic neurotransmission in this region as a potential mechanism underlying these deficits.

A Role for the Amygdala in Impairments of Affective Behaviors Following Mild Traumatic Brain Injury.

Mild traumatic brain injury (TBI) results in chronic affective disorders such as depression, anxiety, and fear that persist up to years following injury and significantly impair the quality of life for patients. Although a great deal of research has contributed to defining symptoms of mild TBI, there are no adequate drug therapies for brain-injured individuals. Preclinical studies have modeled these deficits in affective behaviors post-injury to understand the underlying mechanisms with a view to developing appropriate treatment strategies. These studies have also unveiled sex differences that contribute to the varying phenotypes associated with each behavior. Although clinical and preclinical studies have viewed these behavioral deficits as separate entities with unique neurobiological mechanisms, mechanistic similarities suggest that a novel approach is needed to advance research on drug therapy. This review will discuss the circuitry involved in the expression of deficits in affective behaviors following mild TBI in humans and animals and provide evidence that the manifestation of impairment in these behaviors stems from an amygdala-dependent emotional processing deficit. It will highlight mechanistic similarities between these different types of affective behaviors that can potentially advance mild TBI drug therapy by investigating treatments for the deficits in affective behaviors as one entity, requiring the same treatment.

Effects of pituitary adenylate cyclase-activating polypeptide isoforms in nucleus accumbens subregions on ethanol drinking.

While limited research has implicated the neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), in problematic alcohol use, the brain regions and isoforms involved in this effect remain to be determined. One region that has been found both to exhibit PACAP binding and, separately, to be involved in ethanol drinking is the nucleus accumbens (NAc). Thus, this study sought to characterize the effect of the PACAP isoforms in the NAc on ethanol drinking under the intermittent-access two-bottle-choice paradigm, in male and female Long-Evans rats. With microinjection into the medial NAc shell, PACAP-27 but not PACAP-38 was found to dose-dependently reduce binge-like ethanol drinking. In contrast, the PACAP receptor antagonist, PACAP (6-27), but not PACAP (6-38), enhanced ethanol drinking. This effect of PACAP was substance specific, as neither isoform in the NAc shell affected binge-like sucrose drinking. It was also anatomically specific, as PACAP-38 rather than PACAP-27 suppressed ethanol drinking when injected into the NAc core, and PACAP-27 instead enhanced drinking when injected into the caudal third of the medial NAc shell. Finally, while PACAP-38 in the NAc shell affected stress-related exploratory behavior, reducing time spent in the light chamber of a light-dark box, PACAP-27 did not significantly affect behavior in a light-dark box or open field. Together, these results, showing that PACAP-27 in the NAc shell attenuates binge-like ethanol drinking without affecting select stress-related behaviors, suggest that compounds related to this PACAP isoform should be investigated as potential novel therapeutics for the treatment of alcohol use disorder.

The Paraventricular Nucleus of the Thalamus Is an Important Node in the Emotional Processing Network.

The paraventricular nucleus of the thalamus (PVT) has for decades been acknowledged to be an important node in the limbic system, but studies of emotional processing generally fail to incorporate it into their investigational framework. Here, we propose that the PVT should be considered as an integral part of the emotional processing network. Through its distinct subregions, cell populations, and connections with other limbic nuclei, the PVT participates in both major features of emotion: arousal and valence. The PVT, particularly the anterior PVT, can through its neuronal activity promote arousal, both as part of the sleep-wake cycle and in response to novel stimuli. It is also involved in reward, being both responsive to rewarding stimuli and itself affecting behavior reflecting reward, likely via specific populations of cells distributed throughout its subregions. Similarly, neuronal activity in the PVT contributes to depression-like behavior, through yet undefined subregions. The posterior PVT in particular demonstrates a role in anxiety-like behavior, generally promoting but also inhibiting this behavior. This subregion is also especially responsive to stressors, and it functions to suppress the stress response following chronic stress exposure. In addition to participating in unconditioned or primary emotional responses, the PVT also makes major contributions to conditioned emotional behavior. Neuronal activity in response to a reward-predictive cue can be detected throughout the PVT, and endogenous activity in the posterior PVT strongly predicts approach or seeking behavior. Similarly, neuronal activity during conditioned fear retrieval is detected in the posterior PVT and its activation facilitates the expression of conditioned fear. Much of this involvement of the PVT in arousal and valence has been shown to occur through the same general afferents and efferents, including connections with the hypothalamus, prelimbic and infralimbic cortices, nucleus accumbens, and amygdala, although a detailed functional map of the PVT circuits that control emotional responses remains to be delineated. Thus, while caveats exist and more work is required, the PVT, through its extensive connections with other prominent nuclei in the limbic system, appears to be an integral part of the emotional processing network.

Kappa-opioid receptor-dependent changes in dopamine and anxiety-like or approach-avoidance behavior occur differentially across the nucleus accumbens shell rostro-caudal axis.

Neural circuit engagement within the nucleus accumbens (NAc) shell is implicated in the regulation of both negative and positive affect. Classically, the dynorphin/kappa opioid receptor (KOR) system in the NAc was believed to promote aversion, while dopamine was viewed as interacting with reward behavior, and KOR activation was known to inhibit dopamine release. Recently, however, both the KOR and dopamine systems have, separately, been shown to have differential effects across the rostro-caudal axis of the NAc shell on hedonic responses. Whether or not this is due to interactions between KORs and dopamine, and if it extends to anxiety-like or approach-avoidance behaviors, remains to be determined. In this study, we examined in rats the relationship between the KOR and dopamine systems in both the rostral and caudal NAc shell using ex vivo fast scan cyclic voltammetry and the impact of KOR activation on affective behavior using exploration-based tasks. We report here that activation of KORs in the caudal NAc shell significantly inhibits dopamine release, stimulates rearing behavior in a novel environment, increases anxiety-like or avoidance behavior, and reduces locomotor activity. In contrast, activation of KORs in the rostral NAc shell inhibits dopamine release to a lesser extent and instead reduces anxiety-like behavior or increases approach behavior. Taken together, these results indicate that there is heterogeneity across the rostro-caudal axis of the NAc shell in the effects of KOR stimulation on affective behaviors, and they suggest that this might be due to differences in KOR control over dopamine release.

Heightened Exploratory Behavior Following Chronic Excessive Ethanol Drinking: Mediation by Neurotensin Receptor Type 2 in the Anterior Paraventricular Thalamus.

BACKGROUND: Chronic, excessive alcohol drinkers, even without dependence, can exhibit changes in behavior and neurochemical systems. Identifying these changes and their relationship with one another could provide novel avenues for the prevention and treatment of alcohol use disorder. We recently demonstrated, in rats, that neurotensin (NTS) in the paraventricular thalamus (PVT) regulates excessive ethanol (EtOH) drinking. Here, we investigate the effects of chronic EtOH drinking on the PVT-NTS system and its contribution to EtOH-induced behavioral changes. METHODS: We gave adult male Long-Evans rats 20% EtOH under the intermittent access 2-bottle-choice paradigm or maintained them on chow and water for up to 11 weeks. Prior to EtOH exposure and following several weeks of access, during acute abstinence, we tested these groups for multiple behaviors. In the 12th week, during acute abstinence, we examined gene expression and peptide levels of NTS and its receptors in the anterior and posterior subregions of the PVT. Finally, in chronic EtOH drinkers, during acute abstinence, we microinjected the NTS receptor type 2 (NTS2R) agonist, JMV-431, in the anterior PVT (aPVT) and examined subsequent EtOH intake and behavior. RESULTS: Following chronic intermittent EtOH access, rats were classified by cluster analysis as high or low EtOH drinkers. High EtOH drinkers spent more time in the light chamber of a light-dark box and open arms of an elevated plus maze and entered fewer familiar holes in a hole-board apparatus. These differences were absent prior to EtOH exposure but were detectable as early as 4 weeks into drinking. Time in the light chamber following chronic drinking also predicted level of subsequent drinking. High EtOH drinkers also showed elevated protein levels of NTS2R in the aPVT, and pharmacological stimulation of aPVT NTS2R in low drinkers mimicked the increased time spent in the light chamber that was observed in high drinkers. CONCLUSIONS: Our findings suggest that chronic, excessive, but not lower level, EtOH drinking induces heightened or flexible exploratory behavior, which predicts future EtOH drinking and is partly mediated by elevated NTS2R signaling in the aPVT. These EtOH-induced alterations represent adaptations that could perpetuate excessive drinking and lead to the development of EtOH dependence.

Progesterone treatment following traumatic brain injury in the 11-day-old rat attenuates cognitive deficits and neuronal hyperexcitability in adolescence.

Traumatic brain injury (TBI) in children younger than 4 years old results in cognitive and psychosocial deficits in adolescence and adulthood. At 4 weeks following closed head injury on postnatal day 11, male and female rats exhibited impairment in novel object recognition memory (NOR) along with an increase in open arm time in the elevated plus maze (EPM), suggestive of risk-taking behaviors. This was accompanied by an increase in intrinsic excitability and frequency of spontaneous excitatory post-synaptic currents (EPSCs), and a decrease in the frequency of spontaneous inhibitory post-synaptic currents in layer 2/3 neurons within the medial prefrontal cortex (PFC), a region that is implicated in both object recognition and risk-taking behaviors. Treatment with progesterone for the first week after brain injury improved NOR memory at the 4-week time point in both sham and brain-injured rats and additionally attenuated the injury-induced increase in the excitability of neurons and the frequency of spontaneous EPSCs. The effect of progesterone on cellular excitability changes after injury may be related to its ability to decrease the mRNA expression of the ß3 subunit of the voltage-gated sodium channel and increase the expression of the neuronal excitatory amino acid transporter 3 in the medial PFC in sham- and brain-injured animals and also increase glutamic acid decarboxylase mRNA expression in sham- but not brain-injured animals. Progesterone treatment did not affect injury-induced changes in the EPM test. These results demonstrate that administration of progesterone immediately after TBI in 11-day-old rats reduces cognitive deficits in adolescence, which may be mediated by progesterone-mediated regulation of excitatory signaling mechanisms within the medial PFC.

Expression and Distribution of Neuropeptide-Expressing Cells Throughout the Rodent Paraventricular Nucleus of the Thalamus.

The paraventricular nucleus of the thalamus (PVT) has been shown to make significant contributions to affective and motivated behavior, but a comprehensive description of the neurochemicals expressed in the cells of this brain region has never been presented. While the PVT is believed to be composed of projection neurons that primarily use as their neurotransmitter the excitatory amino acid, glutamate, several neuropeptides have also been described in this brain region. In this review article, we combine published literature with our observations from the Allen Brain Atlas to describe in detail the expression and distribution of neuropeptides in cells throughout the mouse and rat PVT, with a special focus on neuropeptides known to be involved in behavior. Several themes emerge from this investigation. First, while the majority of neuropeptides are expressed across the antero-posterior axis of the PVT, they generally exist in a gradient, in which expression is most dense but not exclusive in either the anterior or posterior PVT, although other neuropeptides display somewhat more equal expression in the anterior and posterior PVT but have reduced expression in the middle PVT. Second, we find overall that neuropeptides involved in arousal are more highly expressed in the anterior PVT, those involved in depression-like behavior are more highly expressed in the posterior PVT, and those involved in reward are more highly expressed in the medial PVT, while those involved in the intake of food and drugs of abuse are distributed throughout the PVT. Third, the pattern and content of neuropeptide expression in mice and rats appear not to be identical, and many neuropeptides found in the mouse PVT have not yet been demonstrated in the rat. Thus, while significantly more work is required to uncover the expression patterns and specific roles of individual neuropeptides in the PVT, the evidence thus far supports the existence of a diverse yet highly organized system of neuropeptides in this nucleus. Determined in part by their location within the PVT and their network of projections, the function of the neuropeptides in this system likely involves intricate coordination to influence both affective and motivated behavior.

Orexin/hypocretin and dysregulated eating: Promotion of foraging behavior.

At its discovery, orexin/hypocretin (OX) was hypothesized to promote food intake. Subsequently, with the identification of the participation of OX in numerous other phenomena, including arousal and drug seeking, this neuropeptide was proposed to be involved in highly motivated behaviors. The present review develops the hypothesis that the primary evolutionary function of OX is to promote foraging behavior, seeking for food under conditions of limited availability. Thus, it will first describe published literature on OX and homeostatic food intake, which shows that OX neurons are activated by conditions of food deprivation and in turn stimulate food intake. Next, it will present literature on excessive and binge-like food intake, which demonstrates that OX stimulates both intake and willingness to work for palatable food. Importantly, studies show that binge-like eating can be inhibited by OX antagonists at doses far lower than those required to suppress homeostatic intake (3 mg/kg vs. 30 mg/kg), suggesting that an OX-based pharmacotherapy, at the right dose, could specifically control dysregulated eating. Finally, the review will discuss the role of OX in foraging behavior, citing literature which shows that OX neurons, which are activated during the anticipation of food reward, can promote a number of phenomena involved in successful foraging, including food-anticipatory locomotor behavior, olfactory sensitivity, visual attention, spatial memory, and mastication. Thus, OX may promote homeostatic eating, as well as binge eating of palatable food, due to its ability to stimulate and coordinate the activities involved in foraging behavior.