Midbrain glutamatergic circuit mechanism of resilience to socially transferred allodynia in male mice.

The potential brain mechanism underlying resilience to socially transferred allodynia remains unknown. Here, we utilize a well-established socially transferred allodynia paradigm to segregate male mice into pain-susceptible and pain-resilient subgroups. Brain screening results show that ventral tegmental area glutamatergic neurons are selectively activated in pain-resilient mice as compared to control and pain-susceptible mice. Chemogenetic manipulations demonstrate that activation and inhibition of ventral tegmental area glutamatergic neurons bi-directionally regulate resilience to socially transferred allodynia. Moreover, ventral tegmental area glutamatergic neurons that project specifically to the nucleus accumbens shell and lateral habenula regulate the development and maintenance of the pain-resilient phenotype, respectively. Together, we establish an approach to explore individual variations in pain response and identify ventral tegmental area glutamatergic neurons and related downstream circuits as critical targets for resilience to socially transferred allodynia and the development of conceptually innovative analgesics.

Chronic social stress blunts core body temperature and molecular rhythms of Rbm3 and Cirbp in mouse lateral habenula.

Chronic social stress in mice causes behavioural and physiological changes that result in perturbed rhythms of body temperature, activity and sleep-wake cycle. To further understand the link between mood disorders and temperature rhythmicity in mice that are resilient or susceptible to stress, we measured core body temperature (Tcore) before and after exposure to chronic social defeat stress (CSDS). We found that Tcore amplitudes of stress-resilient and susceptible mice are dampened during exposure to CSDS. However, following CSDS, resilient mice recovered temperature amplitude faster than susceptible mice. Furthermore, the interdaily stability (IS) of temperature rhythms was fragmented in stress-exposed mice during CSDS, which recovered to control levels following stress. There were minimal changes in locomotor activity after stress exposure which correlates with regular rhythmic expression of Prok2 - an output signal of the suprachiasmatic nucleus. We also determined that expression of thermosensitive genes Rbm3 and Cirbp in the lateral habenula (LHb) were blunted 1 day after CSDS. Rhythmic expression of these genes recovered 10 days later. Overall, we show that CSDS blunts Tcore and thermosensitive gene rhythms. Tcore rhythm recovery is faster in stress-resilient mice, but Rbm3 and Cirbp recovery is uniform across the phenotypes.

Neural and molecular investigation into the paraventricular thalamic-nucleus accumbens circuit for pain sensation and non-opioid analgesia.

The paucity of medications with novel mechanisms for pain treatment combined with the severe adverse effects of opioid analgesics has led to an imperative pursuit of non-opioid analgesia and a better understanding of pain mechanisms. Here, we identify the putative glutamatergic inputs from the paraventricular thalamic nucleus to the nucleus accumbens (PVTGlut→NAc) as a novel neural circuit for pain sensation and non-opioid analgesia. Our in vivo fiber photometry and in vitro electrophysiology experiments found that PVTGlut→NAc neuronal activity increased in response to acute thermal/mechanical stimuli and persistent inflammatory pain. Direct optogenetic activation of these neurons in the PVT or their terminals in the NAc induced pain-like behaviors. Conversely, inhibition of PVTGlut→NAc neurons or their NAc terminals exhibited a potent analgesic effect in both naïve and pathological pain mice, which could not be prevented by pretreatment of naloxone, an opioid receptor antagonist. Anterograde trans-synaptic optogenetic experiments consistently demonstrated that the PVTGlut→NAc circuit bi-directionally modulates pain behaviors. Furthermore, circuit-specific molecular profiling and pharmacological studies revealed dopamine receptor 3 as a candidate target for pain modulation and non-opioid analgesic development. Taken together, these findings provide a previously unknown neural circuit for pain sensation and non-opioid analgesia and a valuable molecular target for developing future safer medication.

Encore: Behavioural animal models of stress, depression and mood disorders.

Animal studies over the past two decades have led to extensive advances in our understanding of pathogenesis of depressive and mood disorders. Among these, rodent behavioural models proved to be of highest informative value. Here, we present a comprehensive overview of the most popular behavioural models with respect to physiological, circuit, and molecular biological correlates. Behavioural stress paradigms and behavioural tests are assessed in terms of outcomes, strengths, weaknesses, and translational value, especially in the domain of pharmacological studies.

Sleep-wake dynamics pre- and post-exposure to chronic social stress.

An analytical approach combining the statistical distributions of the sleep-wake bouts and the Markov transition matrix is used to explain the under-examined association between the microarchitecture of the sleep-wake cycle and susceptibility to chronic social stress in C57BL/6J mice. We separated the sleep-wake transitions into distinct sleep-wake sequences, NREM↔Wake and NREM→REM→Wake, which are controlled by independent neural circuits. Our findings imply greater pull toward the wake leading to early termination and fragmentation of the sleep bouts in the light in both sleep-wake sequences pre- and post-stress. Moreover, the stability of NREM in the NREM↔Wake transition was lower, and the probability of transitioning to wake was higher in susceptible relative to resilient or stress-naïve mice pre- and post-stress. Our findings help elucidate the mechanistic interplay between sleep and mood by suggesting the potential neural underpinnings of sleep disturbances responsible the aberrant transitions of sleep-wake bouts exhibited by the stress-susceptible phenotype.

The Resilient Phenotype Induced by Prophylactic Ketamine Exposure During Adolescence Is Mediated by the Ventral Tegmental Area-Nucleus Accumbens Pathway.

BACKGROUND: Major depressive disorder is prevalent in children and adolescents and is associated with a high degree of morbidity throughout life, with potentially devastating personal consequences and public health impact. The efficacy of ketamine (KET) as an antidepressant has been demonstrated in adolescent rodents; however, the neurobiological mechanisms underlying these effects are unknown. Recent evidence showed that KET reverses stress-induced (i.e., depressive-like) deficits within major mesocorticolimbic regions, such as the prefrontal cortex, nucleus accumbens (NAc), and hippocampus, in adult rodents. However, little is known about KET's effect in the ventral tegmental area (VTA), which provides the majority of dopaminergic input to these brain regions. METHODS: We characterized behavioral, biochemical, and electrophysiological effects produced by KET treatment in C57BL/6J male mice during adolescence (n = 7-10 per condition) within the VTA and its major projection regions, namely, the NAc and prefrontal cortex. Subsequently, molecular targets within the VTA-NAc projection were identified for viral gene transfer manipulations to recapitulate the effects of stress or KET treatment. RESULTS: Repeated KET treatment produced a robust proresilient response to chronic social defeat stress. This effect was largely driven by Akt signaling activity within the VTA and NAc, and it could be blocked or recapitulated through direct Akt-viral-mediated manipulation. Additionally, we found that the KET-induced resilient phenotype is dependent on VTA-NAc, but not VTA-prefrontal cortex, pathway activity. CONCLUSIONS: These findings indicate that KET exposure during adolescence produces a proresilient phenotype mediated by changes in Akt intracellular signaling and altered neuronal activity within the VTA-NAc pathway.

Prolonged Exposure to Social Stress Impairs Homeostatic Sleep Regulation.

Stress and sleep are tightly regulated as a result of the substantial overlap in neurotransmitter signaling and regulatory pathways between the neural centers that modulate mood and sleep-wake cycle. The chronicity of the stressor and variability in coping with it are major determinants of the psychiatric outcomes and subsequent effect on sleep. The regulation of sleep is mediated by the interaction of a homeostatic and a circadian process according to the two-process model. Chronic stress induces stress-related disorders which are associated with deficient sleep homeostasis. However, little is known about how chronic stress affects sleep homeostasis and whether the differences in adaptation to stress distinctively influence sleep. Therefore, we assessed sleep homeostasis in C57BL6/J mice following exposure to 15-d of chronic social defeat stress. We implemented wake:sleep ratio as a behavioral correlate of sleep pressure. Both stress-resilient and stress-susceptible mice displayed deficient sleep homeostasis in post-stress baseline sleep. This was due to poor temporal correlation between frontal slow wave activity (SWA) power and sleep pressure in the dark/active phase. Moreover, the buildup rate of sleep pressure in the dark was lower in susceptible mice in comparison to stress-naïve mice. Additionally, 4-h SD in the dark caused a deficient sleep recovery response in susceptible mice characterized by non-rapid eye movement (NREM) sleep loss. Our findings provide evidence of deficient homeostatic sleep process (S) in baseline sleep in stress-exposed mice, while impaired sleep recovery following a mild enforced wakefulness experienced during the dark was only detected in stress-susceptible mice. This alludes to the differential homeostatic adaptation to stress between susceptible and resilient mice and its effect on sleep regulation.

Blunted diurnal firing in lateral habenula projections to dorsal raphe nucleus and delayed photoentrainment in stress-susceptible mice.

Daily rhythms are disrupted in patients with mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the 15-day chronic social defeat stress (CSDS) paradigm and in vitro slice electrophysiology, we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb→DRN) and unlabeled DRN cells. We also performed optogenetic experiments to investigate if increased firing in cellsLHb→DRN during exposure to a weak 7-day social defeat stress (SDS) paradigm induces stress-susceptibility. Last, we investigated whether exposure to CSDS affected the ability of mice to photoentrain to a new light-dark (LD) cycle. The cellsLHb→DRN and unlabeled DRN cells of stress-susceptible mice express greater blunted diurnal firing compared to stress-näive (control) and stress-resilient mice. Daytime optogenetic activation of cellsLHb→DRN during SDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that exposure to strong stressors induces blunted daily rhythms in firing in cellsLHb→DRN, DRN cells and decreases the initial rate of photoentrainment in susceptible-mice. In contrast, resilient-mice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb→DRN and also show rapid photoentrainment to a new LD cycle.

What it takes to be at the top: The interrelationship between chronic social stress and social dominance.

INTRODUCTION: Dominance hierarchies of social animal groups are very sensitive to stress. Stress experienced prior to social interactions between conspecifics may be a determinant of their future social dynamics. Additionally, long-term occupancy of a specific hierarchical rank can have psychophysiological effects which increase vulnerability to future stressors. METHODS: We aimed to delineate differential effects of stress acting before or after hierarchy formation. We studied whether exposure to the chronic social defeat stress (CSDS) paradigm before a two-week-long hierarchy formation affected the attainment of a dominant status using the social confrontation tube test (TT). These animals were singly housed for at least one week before CSDS to decrease confounding effects of prior hierarchy experience. Additionally, we investigated whether social rank predicted vulnerability to CSDS, measured by a social interaction test. RESULTS: In TT, mice termed as dominant (high rank) win the majority of social confrontations, while the subordinates (low rank) lose more often. Within newly established hierarchies of stress-naïve mice, the subordinate, but not dominant, mice exhibited significantly greater avoidance of novel social targets. However, following exposure to CSDS, both lowest- and highest-ranked mice exhibited susceptibility to stress as measured by decreased interactions with a novel social target. In contrast, after CSDS, both stress-susceptible (socially avoidant) and stress-resilient (social) mice were able to attain dominant ranks in newly established hierarchies. CONCLUSION: These results suggest that the response to CSDS did not determine social rank in new cohorts, but low-status mice in newly established groups exhibited lower sociability to novel social targets. Interestingly, exposure of a hierarchical social group to chronic social stress led to stress susceptibility in both high- and low-status mice as measured by social interaction.

Abnormal Sleep Signals Vulnerability to Chronic Social Defeat Stress.

There is a tight association between mood and sleep as disrupted sleep is a core feature of many mood disorders. The paucity in available animal models for investigating the role of sleep in the etiopathogenesis of depression-like behaviors led us to investigate whether prior sleep disturbances can predict susceptibility to future stress. Hence, we assessed sleep before and after chronic social defeat (CSD) stress. The social behavior of the mice post stress was classified in two main phenotypes: mice susceptible to stress that displayed social avoidance and mice resilient to stress. Pre-CSD, mice susceptible to stress displayed increased fragmentation of Non-Rapid Eye Movement (NREM) sleep, due to increased switching between NREM and wake and shorter average duration of NREM bouts, relative to mice resilient to stress. Logistic regression analysis showed that the pre-CSD sleep features from both phenotypes were separable enough to allow prediction of susceptibility to stress with >80% accuracy. Post-CSD, susceptible mice maintained high NREM fragmentation while resilient mice exhibited high NREM fragmentation, only in the dark. Our findings emphasize the putative role of fragmented NREM sleep in signaling vulnerability to stress.

Role of Mesolimbic Brain-Derived Neurotrophic Factor in Depression.

Brain-derived neurotrophic factor (BDNF) is widely accepted as being critical for neural and synaptic plasticity throughout the nervous system. Recent work has shown that BDNF in the mesolimbic dopamine (DA) circuit, originating in ventral tegmental area DA neurons that project to the nucleus accumbens, is crucial in the development of depressive-like behaviors following exposure to chronic social defeat stress in mice. Whereas BDNF modulates DA signaling in encoding responses to acute defeat stress, BDNF signaling alone appears to be responsible for the behavioral effects after chronic social defeat stress. Very different patterns are seen with another widely used chronic stress paradigm in mice, chronic mild stress (also known as chronic variable or unpredictable stress), where DA signaling, but not BDNF signaling, is primarily responsible for the behavioral effects observed. This review discusses the molecular, cellular, and circuit basis of this dramatic discrepancy, which appears to involve the nature of the stress, its severity and duration, and its effects on distinct cell types within the ventral tegmental area-to-nucleus accumbens mesolimbic circuit.

α1- and ß3-Adrenergic Receptor-Mediated Mesolimbic Homeostatic Plasticity Confers Resilience to Social Stress in Susceptible Mice.

BACKGROUND: Homeostatic plasticity in mesolimbic dopamine (DA) neurons plays an essential role in mediating resilience to social stress. Recent evidence implicates an association between stress resilience and projections from the locus coeruleus (LC) to the ventral tegmental area (VTA) (LC→VTA) DA system. However, the precise circuitry and molecular mechanisms of the homeostatic plasticity in mesolimbic DA neurons mediated by the LC→VTA circuitry, and its role in conferring resilience to social defeat stress, have not been described. METHODS: In a well-established chronic social defeat stress model of depression, using projection-specific electrophysiological recordings and optogenetic, pharmacological, and molecular profiling techniques, we investigated the functional role and molecular basis of an LC→VTA circuit in conferring resilience to social defeat stress. RESULTS: We found that LC neurons projecting to the VTA exhibit enhanced firing activity in resilient, but not susceptible, mice. Optogenetically mimicking this firing adaptation in susceptible mice reverses their depression-related behaviors, and induces reversal of cellular hyperactivity and homeostatic plasticity in VTA DA neurons projecting to the nucleus accumbens. Circuit-specific molecular profiling studies reveal that α1- and ß3-adrenergic receptors are highly expressed in VTA→nucleus accumbens DA neurons. Pharmacologically activating these receptors induces similar proresilient effects at the ion channel and cellular and behavioral levels, whereas antagonizing these receptors blocks the proresilient effect of optogenetic activation of LC→VTA circuit neurons in susceptible mice. CONCLUSIONS: These findings reveal a key role of the LC→VTA circuit in mediating homeostatic plasticity in stress resilience and reveal α1- and ß3-adrenergic receptors as new molecular targets for therapeutically promoting resilience.

The role of dopamine in mood disorders and the associated changes in circadian rhythms and sleep-wake cycle.

Dopamine is primarily produced in the substantia nigra (SN) and the ventral tegmentum area (VTA) in the brain. It plays a well-established role in the motor control, reward, mood regulation and addiction behaviour. Dopamine release has been shown to be regulated by the circadian clock and hence, plays a regulatory role in the sleep-wake cycle. Clinically, dopaminergic agents have been widely used to modulate alertness. The following review offers a demonstration of the heterogeneous dopamine system in the brain and the various studies investigating the circadian rhythmicity of the dopamine system and its regulation of sleep-wake behaviour. Additionally, it suggests a potential link between the circadian clock and the sleep-wake cycle in mood regulation through the dopaminergic system.

Modeling of inhomogeneous electromagnetic fields in the nervous system: a novel paradigm in understanding cell interactions, disease etiology and therapy.

All major processes in the nervous system depend on interactions between cells and nerve fibers. In this work we present a novel model of inhomogeneous electromagnetic fields originating from nerve fibers and delineate their influence on cells. By expanding Hodgkin-Huxley's applied current into axial current, governed by[Formula: see text], we reveal that cell-with-neuron interactions are regulated by the strength of the electromagnetic fields, which are homogeneous up to 2.066 µm or 6.606 µm away from neurilemma and axolemma, respectively. At the nodes of Ranvier, these fields reach strengths of 3.0 × 10-12T, while at the myelinated segments they only peak at 2.3 × 10-12T. These are the same fields which are, due to inhomogeneity, detected as 1,000 times weaker by magnetoencephalography. Considering the widespread occurrence of neurodegenerative disorders, our model reveals that a 50% demyelination increases the field strength by 0.35 × 10-12T, while a complete demyelination increases it by 0.7 × 10-12T. Since this suggests that the inhomogeneous electromagnetic fields around neurons play a role in physiological and pathological processes, including cell-to-neuron and cell-to-cell communication, their improved understanding opens up new therapeutic strategies based on electromagnetic field modulation or cell's surface charge alteration.

Author Correction: Midbrain circuit regulation of individual alcohol drinking behaviors in mice.

The original version of this Article contained an error in the spelling of the author Scott Edwards, which was incorrectly given as Scott Edward. This has now been corrected in both the PDF and HTML versions of the Article.

Midbrain circuit regulation of individual alcohol drinking behaviors in mice.

Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors.

Basal forebrain projections to the lateral habenula modulate aggression reward.

Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

KCNQ channel openers reverse depressive symptoms via an active resilience mechanism.

Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K(+)) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K(+) channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms.

Neuronal correlates of depression.

Major depressive disorder (MDD) is a common psychiatric disorder effecting approximately 121 million people worldwide and recent reports from the World Health Organization (WHO) suggest that it will be the leading contributor to the global burden of diseases. At present, the most commonly used treatment strategies are still based on the monoamine hypothesis that has been the predominant theory in the last 60 years. Clinical observations show that only a subset of depressed patients exhibits full remission when treated with classical monoamine-based antidepressants together with the fact that patients exhibit multiple symptoms suggest that the pathophysiology leading to mood disorders may differ between patients. Accumulating evidence indicates that depression is a neural circuit disorder and that onset of depression may be located at different regions of the brain involving different transmitter systems and molecular mechanisms. This review synthesises findings from rodent studies from which emerges a role for different, yet interconnected, molecular systems and associated neural circuits to the aetiology of depression.