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Comparatively little is known about how new instrumental actions are encoded in the brain. Using whole-brain c-Fos mapping, we show that neural activity is increased in the anterior dorsolateral striatum (aDLS) of mice that successfully learn a new lever-press response to earn food rewards. Post-learning chemogenetic inhibition of aDLS disrupts consolidation of the new instrumental response. Similarly, post-learning infusion of the protein synthesis inhibitor anisomycin into the aDLS disrupts consolidation of the new response. Activity of D1 receptor-expressing medium spiny neurons (D1-MSNs) increases and D2-MSNs activity decreases in the aDLS during consolidation. Chemogenetic inhibition of D1-MSNs in aDLS disrupts the consolidation process whereas D2-MSN inhibition strengthens consolidation but blocks the expression of previously learned habit-like responses. These findings suggest that D1-MSNs in the aDLS encode new instrumental actions whereas D2-MSNs oppose this new learning and instead promote expression of habitual actions. New instrumental learning occurs through an unexpected delivery of a rewarding stimulus or the withdrawal of a punishing stimulus. The authors show that D1 receptor-expressing medium spiny neurons (MSNs) in the anterior dorsolateral striatum encode newly learned instrumental actions whereas D2 MSNs promote the expression of habitual actions.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula–pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions. The transcription factor TCF7L2 mediates two important responses to nicotine in the medial habenula region of the rodent brain: aversion to nicotine, and regulation of blood sugar levels through a polysynaptic habenula–pancreas circuit.

Early-life stress is a main contributory factor to the onset of depression. Treatments remain inadequate and as such, a large unmet medical need for novel therapeutics remains. Impeding advancement is the poor understanding of the molecular pathology. microRNAs (miRNAs) are novel regulators of gene expression. A paucity of information regarding their role in depressive pathology and antidepressant action remains. This study investigated changes to hippocampal miRNA levels induced via early-life stress in Sprague–Dawley rats and whether antidepressant treatments could reverse these changes. Investigated were the selective serotonin reuptake inhibitor fluoxetine, the rapid acting N-methyl-d-aspartate receptor antagonist ketamine and electroconvulsive shock therapy (ECT). Microarray analysis revealed early-life stress affected the expression of multiple hippocampal miRNAs. Antidepressant treatments reversed some of these effects including a stress-induced change to miR-451. Ketamine and ECT possessed the highest number of common targets suggesting convergence on common pathways. Interestingly all three treatments possessed miR-598-5p as a common target. This demonstrates that changes to hippocampal miRNA expression may represent an important component of stress-induced pathology and antidepressant action may reverse these.

RationalePost-traumatic stress disorder (PTSD) is a devastating anxiety-related disorder which develops subsequent to a severe psychologically traumatic event. Only ~ 9% of people who experience such a trauma develop PTSD. It is clear that a number of factors, including genetics, influence whether an individual will develop PTSD subsequent to a trauma. The 129S1/SvImJ (S1) inbred mouse strain displays poor fear extinction and may be useful to model this specific aspect of PTSD. The metabotropic glutamate receptor 7 (mGlu7 receptor) has previously been shown to be involved in cognitive processes and anxiety-like behaviour placing it in a key position to regulate fear extinction processes. We sought to compare mGlu7 receptor mRNA levels in the S1 strain with those in the robustly extinguishing C57BL/6J (B6) inbred strain using in situ hybridisation (ISH) in three brain regions associated with fear extinction: the amygdala, hippocampus and prefrontal cortex (PFC).ResultsCompared to the B6 strain, S1 mice had increased mGlu7 receptor mRNA levels in the lateral amygdala (LA) and basolateral amygdala (BLA) subdivisions. An increase was also seen in the hippocampal CA1 and CA3 subregions of S1 mice. No difference in mGlu7 receptor levels were seen in the central nucleus (CeA) of the amygdala, dentate gyrus (DG) of the hippocampus or prefrontal cortex.ConclusionsThese data show altered mGlu7 receptor expression in key brain regions associated with fear extinction in two different inbred mouse strains which differ markedly in their fear extinction behaviour. Altered mGlu7 receptor levels may contribute to the deficit fear extinction processes seen in fear extinction in the S1 strain.

Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysis-based pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat, thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier (BBB) in vivo. The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.

Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.

The discovery that interactions between two stress-associated neuropeptide hormones regulate binge drinking in mice provides insight into the biological mechanisms that underpin the bingeing cycle.

Recent preclinical studies have revealed a functionally important role for the drug efflux pump P‐glycoprotein (P‐gp) at the blood–brain barrier in limiting brain levels and thus antidepressant‐like activity of certain antidepressant drugs. Specifically, acute administration of P‐gp inhibitors, such as verapamil and cyclosporin A (CsA), has been shown to augment brain concentrations and functional activity of the antidepressant escitalopram in rodents. However, depression is a chronic disorder and current treatments require prolonged administration to elicit their full therapeutic effect. Thus, it is important to investigate whether acute findings in relation to P‐gp inhibition translate to chronic paradigms. To this end, the present study investigates whether chronic treatment with the P‐gp inhibitor verapamil and the antidepressant escitalopram results in enhanced brain distribution and antidepressant‐like effects of escitalopram. Verapamil (10 mg·kg−1 i.p.) and escitalopram (0.1 mg·kg−1 i.p.) were administered once daily for 22 days. On the final day of treatment, brain regions and plasma were collected for analysis of cortical and plasma escitalopram concentrations, and to determine the hippocampal expression of genes previously reported to be altered by chronic antidepressant treatment. Verapamil treatment resulted in a greater than twofold increase in brain levels of escitalopram, without altering plasma levels. Neither gene expression analysis nor behavioral testing revealed an augmentation of responses to escitalopram treatment due to verapamil administration. Taken together, these data demonstrate for the first time that P‐gp inhibition can yield elevated brain concentrations of an antidepressant after chronic treatment. The functional relevance of these increased brain levels requires further elaboration.