Jessica J. Walsh

Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons

Ventral tegmental area (VTA) dopamine neurons in the brain’s reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence—in real time—linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA–NAc projection induced resilience, whereas inhibition of the VTA–mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.

Mesolimbic Dopamine Neurons in the Brain Reward Circuit Mediate Susceptibility to Social Defeat and Antidepressant Action

We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10 d) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2 week), but not acute (single dose), treatments with the antidepressant medication fluoxetine (20 mg/kg). Chronic social defeat stress increased hyperpolarization-activated cation current (Ih) in VTA dopamine neurons, an effect that was also normalized by chronic treatment with fluoxetine. As well, local infusion of Ih inhibitors ZD7288 (0.1 μg) or DK-AH 269 (0.6 μg) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individuals responses to chronic stress and antidepressant action.

Role of Vascular Risk Factors and Vascular Dysfunction in Alzheimer's Disease

Recent findings indicate that vascular risk factors and neurovascular dysfunction play integral roles in the pathogenesis of Alzheimers disease. In addition to aging, the most common risk factors for Alzheimers disease are apolipoprotein e4 allele, hypertension, hypotension, diabetes, and hypercholesterolemia. All of these can be characterized by vascular pathology attributed to conditions such as cerebral amyloid angiopathy and subsequent blood-brain barrier dysfunction. Many epidemiological, clinical, and pharmacotherapeutic studies have assessed the associations between such risk factors and Alzheimers disease and have found positive associations between hypertension, hypotension, and diabetes mellitus. However, there are still many conflicting results from these population-based studies, and they should be interpreted carefully. Recognition of these factors and the mechanisms by which they contribute to Alzheimers disease will be beneficial in the current treatment regimens for Alzheimers disease and in the development of future therapies. Here we discuss vascular factors with respect to Alzheimers disease and dementia and review the factors that give rise to vascular dysfunction and contribute to Alzheimers disease.

Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience

Resilient Hyperpolarization Despite constant exposure to all sorts of stressors, most people are resilient and do not develop depression, but we do not understand the neurophysiological underpinnings of stress resilience. Friedman et al. (p. 313) studied this phenomenon in a mouse model of social-defeat stress depression. In the mice they found that, despite apparently pathological levels of hyperpolarization and elevated potassium channel currents in the ventral tegmental area (a structure known to be involved in depression), resilient mice showed normal activity in dopaminergic neurons. Thus, if “depressed” mice were experimentally provoked into hyperpolarization—unexpectedly, they completely reversed depression-related behaviors. Intensifying pathogenic changes paradoxically ameliorate depressive symptoms in mice. Typical therapies try to reverse pathogenic mechanisms. Here, we describe treatment effects achieved by enhancing depression-causing mechanisms in ventral tegmental area (VTA) dopamine (DA) neurons. In a social defeat stress model of depression, depressed (susceptible) mice display hyperactivity of VTA DA neurons, caused by an up-regulated hyperpolarization-activated current (Ih). Mice resilient to social defeat stress, however, exhibit stable normal firing of these neurons. Unexpectedly, resilient mice had an even larger Ih, which was observed in parallel with increased potassium (K+) channel currents. Experimentally further enhancing Ih or optogenetically increasing the hyperactivity of VTA DA neurons in susceptible mice completely reversed depression-related behaviors, an antidepressant effect achieved through resilience-like, projection-specific homeostatic plasticity. These results indicate a potential therapeutic path of promoting natural resilience for depression treatment.

Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors

Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.

Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway

Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context–detecting function of the brains mesolimbic circuit.

Amyloid precursor protein (APP) regulates synaptic structure and function.

The amyloid precursor protein (APP) plays a critical role in Alzheimers disease (AD) pathogenesis. APP is proteolytically cleaved by β- and γ-secretases to generate the amyloid β-protein (Aβ), the core protein component of senile plaques in AD. It is also cleaved by α-secretase to release the large soluble APP (sAPP) luminal domain that has been shown to exhibit trophic properties. Increasing evidence points to the development of synaptic deficits and dendritic spine loss prior to deposition of amyloid in transgenic mouse models that overexpress APP and Aβ peptides. The consequence of loss of APP, however, is unsettled. In this study, we investigated whether APP itself plays a role in regulating synaptic structure and function using an APP knock-out (APP-/-) mouse model. We examined dendritic spines in primary cultures of hippocampal neurons and CA1 neurons of hippocampus from APP-/- mice. In the cultured neurons, there was a significant decrease (~35%) in spine density in neurons derived from APP-/- mice compared to littermate control neurons that were partially restored with sAPPα-conditioned medium. In APP-/- mice in vivo, spine numbers were also significantly reduced but by a smaller magnitude (~15%). Furthermore, apical dendritic length and dendritic arborization were markedly diminished in hippocampal neurons. These abnormalities in neuronal morphology were accompanied by reduction in long-term potentiation. Strikingly, all these changes in vivo were only seen in mice that were 12-15 months in age but not in younger animals. We propose that APP, specifically sAPP, is necessary for the maintenance of dendritic integrity in the hippocampus in an age-associated manner. Finally, these age-related changes may contribute to AD pathology independent of Aβ-mediated synaptic toxicity.

The heterogeneity of ventral tegmental area neurons: Projection functions in a mood-related context

The ventral tegmental area (VTA) in the brains reward circuitry is composed of a heterogeneous population of dopamine, GABA, and glutamate neurons that play important roles in mediating mood-related functions including depression. These neurons project to different brain regions, including the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC), and the amygdala. The functional understanding of these projection pathways has been improved since the extensive use of advanced techniques such as viral-mediated gene transfer, cell-type-specific neurophysiology and circuit-probing optogenetics. In this article, we will discuss the recent progress in understanding these VTA projection-specific functions, focusing on mood-related disorders.

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.

Essential Role of Mesolimbic Brain-Derived Neurotrophic Factor in Chronic Social Stress-Induced Depressive Behaviors.

BACKGROUND Previous work has shown that chronic social defeat stress (CSDS) induces increased phasic firing of ventral tegmental area (VTA) dopamine (DA) neurons that project to the nucleus accumbens (NAc) selectively in mice that are susceptible to the deleterious effects of the stress. In addition, acute optogenetic phasic stimulation of these neurons promotes susceptibility in animals exposed to acute defeat stress. These findings are paradoxical, as increased DA signaling in NAc normally promotes motivation and reward, and the influence of chronic phasic VTA firing in the face of chronic stress is unknown. METHODS We used CSDS with repeated optogenetic activation and pharmacologic manipulations of the mesolimbic VTA-NAc pathway to examine the role of brain-derived neurotrophic factor (BDNF) and DA signaling in depressive-like behaviors. We measured BDNF protein expression and DA release in this model. RESULTS Pharmacologic blockade of BDNF-tyrosine receptor kinase B (TrkB) signaling, but not DA signaling, in NAc prevented CSDS-induced behavioral abnormalities. Chronic optogenetic phasic stimulation of the VTA-NAc circuit during CSDS exacerbated the defeat-induced behavioral symptoms, and these aggravated symptoms were also normalized by BDNF-TrkB blockade in NAc. The aggravated behavioral deficits induced by phasic stimulation of the VTA-NAc pathway were blocked as well by local knockdown of BDNF in VTA. CONCLUSIONS These findings show that BDNF-TrkB signaling, rather than DA signaling, in the VTA-NAc circuit is crucial for facilitating depressive-like outcomes after CSDS and they establish BDNF-TrkB signaling as a pathologic mechanism during periods of chronic stress.