RESUMEN
Impulsive overeating is a common, disabling feature of eating disorders. Both continuous deep brain stimulation (DBS) and responsive DBS, which limits current delivery to pathological brain states, have emerged as potential therapies. We used in vivo fiber photometry in wild-type, Drd1-cre, and A2a-cre mice to 1) assay subtype-specific medium spiny neuron (MSN) activity of the nucleus accumbens (NAc) during hedonic feeding of high-fat food, and 2) examine DBS strategy-specific effects on NAc activity. D1, but not D2, NAc GCaMP activity increased immediately prior to high-fat food approach. Responsive DBS triggered a GCaMP surge throughout the stimulation period and durably reduced high-fat intake. However, with continuous DBS, this surge decayed, and high-fat intake reemerged. Our results argue for a stimulation strategy-dependent modulation of D1 MSNs with a more sustained decrease in consumption with responsive DBS. This study illustrates the important role in vivo imaging can play in understanding effects of such novel therapies.
Asunto(s)
Encéfalo/fisiología , Estimulación Encefálica Profunda/métodos , Conducta Alimentaria/fisiología , Animales , Conducta Impulsiva , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/fisiología , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismoRESUMEN
Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.
Asunto(s)
Trastorno del Espectro Autista/psicología , Trastorno del Espectro Autista/terapia , Núcleo Accumbens/metabolismo , Serotonina/metabolismo , Conducta Social , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 16/genética , Cromosomas de los Mamíferos/genética , Modelos Animales de Enfermedad , Núcleo Dorsal del Rafe/citología , Núcleo Dorsal del Rafe/metabolismo , Humanos , Masculino , Ratones , Vías Nerviosas , Núcleo Accumbens/citología , Optogenética , Sintenía/genéticaRESUMEN
The detailed mechanisms by which dopamine (DA) and serotonin (5-HT) act in the nucleus accumbens (NAc) to influence motivated behaviors in distinct ways remain largely unknown. Here, we examined whether DA and 5-HT selectively modulate excitatory synaptic transmission in NAc medium spiny neurons in an input-specific manner. DA reduced excitatory postsynaptic currents (EPSCs) generated by paraventricular thalamus (PVT) inputs but not by ventral hippocampus (vHip), basolateral amygdala (BLA), or medial prefrontal cortex (mPFC) inputs. In contrast, 5-HT reduced EPSCs generated by inputs from all areas except the mPFC. Release of endogenous DA and 5-HT by methamphetamine (METH) and (±)3,4-methylenedioxymethamphetamine (MDMA), respectively, recapitulated these input-specific synaptic effects. Optogenetic inhibition of PVT inputs enhanced cocaine-conditioned place preference, whereas mPFC input inhibition reduced the enhancement of sociability elicited by MDMA. These findings suggest that the distinct, input-specific filtering of excitatory inputs in the NAc by DA and 5-HT contribute to their discrete behavioral effects.
Asunto(s)
Dopamina/farmacología , Potenciales Postsinápticos Excitadores , Núcleo Accumbens/fisiología , Serotonina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Metanfetamina/farmacología , Ratones Endogámicos C57BL , N-Metil-3,4-metilenodioxianfetamina/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Núcleo Accumbens/efectos de los fármacos , Interacción Social/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
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.
Asunto(s)
Agresión/fisiología , Prosencéfalo Basal/fisiología , Habénula/fisiología , Vías Nerviosas/fisiología , Recompensa , Potenciales de Acción , Animales , Prosencéfalo Basal/citología , Condicionamiento Psicológico/fisiología , Neuronas GABAérgicas/metabolismo , Habénula/citología , Halorrodopsinas/metabolismo , Individualidad , Masculino , Ratones , Modelos Neurológicos , Motivación , Inhibición Neural , Refuerzo en Psicología , Rodopsina/metabolismo , Conducta SocialRESUMEN
Chronic stress in both humans and rodents induces a robust downregulation of neuroligin-2, a key component of the inhibitory synapse, in the NAc that modifies behavioral coping mechanisms and stress resiliency in mice. Here we extend this observation by examining the role of two other inhibitory synapse constituents, vesicular GABA transporter (vGAT) and gephyrin, in the NAc of male mice that underwent chronic social defeat stress (CSDS) and in patients with major depressive disorder (MDD). We first performed transcriptional profiling of vGAT and gephyrin in postmortem NAc samples from a cohort of healthy controls, medicated, and nonmedicated MDD patients. In parallel, we conducted whole-cell electrophysiology recordings in the NAc of stress-susceptible and stress-resilient male mice following 10 d of CSDS. Finally, we used immunohistochemistry to analyze protein levels of vGAT and gephyrin in the NAc of mice after CSDS. We found that decreased vGAT and gephyrin mRNA in the NAc of nonmedicated MDD patients is paralleled by decreased inhibitory synapse markers and decreased frequency of mini inhibitory postsynaptic currents (mIPSC) in the NAc of susceptible mice, indicating a reduction in the number of NAc inhibitory synapses that is correlated with depression-like behavior. Overall, these findings suggest a common state of reduced inhibitory tone in the NAc in depression and stress susceptibility.SIGNIFICANCE STATEMENT Existing studies focus on excitatory synaptic changes after social stress, although little is known about stress-induced inhibitory synaptic plasticity and its relevance for neuropsychiatric disease. These results extend our previous findings on the critical role of impaired inhibitory tone in the NAc following stress and provide new neuropathological evidence for reduced levels of inhibitory synaptic markers in human NAc from nonmedicated major depressive disorder patients. This finding is corroborated in stress-susceptible male mice that have undergone chronic social defeat stress, a mouse model of depression, at both the level of synaptic function and protein expression. These data support the hypothesis that reduced inhibitory synaptic transmission within the NAc plays a critical role in the stress response.
Asunto(s)
Depresión/metabolismo , Potenciales Postsinápticos Inhibidores , Núcleo Accumbens/fisiopatología , Derrota Social , Estrés Psicológico/metabolismo , Adulto , Anciano , Animales , Depresión/fisiopatología , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Persona de Mediana Edad , Núcleo Accumbens/metabolismo , Estrés Psicológico/fisiopatología , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/genética , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismoRESUMEN
Reward hypersensitization is a common feature of neuropsychiatric disorders, manifesting as impulsivity for anticipated incentives. Temporally specific changes in activity within the nucleus accumbens (NAc), which occur during anticipatory periods preceding consummatory behavior, represent a critical opportunity for intervention. However, no available therapy is capable of automatically sensing and therapeutically responding to this vulnerable moment in time when anticipation-related neural signals may be present. To identify translatable biomarkers for an off-the-shelf responsive neurostimulation system, we record local field potentials from the NAc of mice and a human anticipating conventional rewards. We find increased power in 1- to 4-Hz oscillations predominate during reward anticipation, which can effectively trigger neurostimulation that reduces consummatory behavior in mice sensitized to highly palatable food. Similar oscillations are present in human NAc during reward anticipation, highlighting the translational potential of our findings in the development of a treatment for a major unmet need.
Asunto(s)
Conducta Consumatoria/fisiología , Ritmo Delta/fisiología , Núcleo Accumbens/fisiología , Animales , Femenino , Humanos , Masculino , RatonesRESUMEN
Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Dominación-Subordinación , Proteínas del Tejido Nervioso/metabolismo , Núcleo Accumbens/metabolismo , Estrés Psicológico/fisiopatología , Agresión , Animales , Antidepresivos/farmacología , Conducta Animal , Línea Celular , Modelos Animales de Enfermedad , Heterocigoto , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/metabolismo , ARN Mensajero/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Conducta Social , Sinapsis/metabolismoRESUMEN
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.
Asunto(s)
Depresión/fisiopatología , Neuronas Dopaminérgicas/metabolismo , Mesencéfalo/citología , Conducta Social , Estrés Psicológico/fisiopatología , Animales , Depresión/etiología , Preferencias Alimentarias , Masculino , Ratones , Vías Nerviosas , Núcleo Accumbens/fisiología , Optogenética , Fenotipo , Corteza Prefrontal/fisiología , Estrés Psicológico/complicaciones , Sacarosa/administración & dosificación , Factores de Tiempo , Área Tegmental Ventral/fisiologíaRESUMEN
Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6(-/-)) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6(-/-) BM chimeric and IL-6(-/-) mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities.
Asunto(s)
Trastornos de Ansiedad/inmunología , Conducta Animal , Interleucina-6/inmunología , Estrés Psicológico/inmunología , Aloinjertos , Animales , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/patología , Trasplante de Médula Ósea , Susceptibilidad a Enfermedades/inmunología , Susceptibilidad a Enfermedades/patología , Interleucina-6/genética , Ratones , Ratones Noqueados , Estrés Psicológico/genética , Estrés Psicológico/patología , Factores de Tiempo , Quimera por Trasplante/genética , Quimera por Trasplante/inmunologíaRESUMEN
Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability. SIGNIFICANCE STATEMENT: Women have a higher incidence of depression than men. However, preclinical models, the first step in developing new diagnostics and therapeutics, have been performed mainly on male subjects. Using a stress-based animal model of depression that causes behavioral effects in females but not males, we demonstrate a sex-specific transcriptional profile in brain reward circuitry. This transcriptional profile can be altered by removal of an epigenetic mechanism, which normally suppresses DNA transcription, creating a hybrid male/female transcriptional pattern. Removal of this epigenetic mechanism also induces behavioral resilience to stress in females. These findings shed new light onto molecular factors controlling sex differences in stress response.
Asunto(s)
Núcleo Accumbens/fisiopatología , Resiliencia Psicológica , Estrés Psicológico/genética , Estrés Psicológico/psicología , Transcriptoma/genética , Animales , Ansiedad/genética , Ansiedad/psicología , Enfermedad Crónica , ADN (Citosina-5-)-Metiltransferasas/biosíntesis , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Conducta Alimentaria , Femenino , Regulación Enzimológica de la Expresión Génica/genética , Técnicas de Sustitución del Gen , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora , Represión Psicológica , Caracteres Sexuales , Natación/psicologíaRESUMEN
It is well established that behavioral sensitization to cocaine is accompanied by increased spine density and AMPA receptor (AMPAR) transmission in the nucleus accumbens (NAc), but two major questions remain unanswered. Are these adaptations mechanistically coupled? And, given that they can be dissociated from locomotor sensitization, what is their functional significance? We tested the hypothesis that the guanine-nucleotide exchange factor Kalirin-7 (Kal-7) couples cocaine-induced AMPAR and spine upregulation and that these adaptations underlie sensitization of cocaine's incentive-motivational properties-the properties that make it "wanted." Rats received eight daily injections of saline or cocaine. On withdrawal day 14, we found that Kal-7 levels and activation of its downstream effectors Rac-1 and PAK were increased in the NAc of cocaine-sensitized rats. Furthermore, AMPAR surface expression and spine density were increased, as expected. To determine whether these changes require Kal-7, a lentiviral vector expressing Kal-7 shRNA was injected into the NAc core before cocaine exposure. Knocking down Kal-7 abolished the AMPAR and spine upregulation normally seen during cocaine withdrawal. Despite the absence of these adaptations, rats with reduced Kal-7 levels developed locomotor sensitization. However, incentive sensitization, which was assessed by how rapidly rats learned to self-administer a threshold dose of cocaine, was severely impaired. These results identify a signaling pathway coordinating AMPAR and spine upregulation during cocaine withdrawal, demonstrate that locomotor and incentive sensitization involve divergent mechanisms, and link enhanced excitatory transmission in the NAc to incentive sensitization.
Asunto(s)
Cocaína/administración & dosificación , Espinas Dendríticas/metabolismo , Factores de Intercambio de Guanina Nucleótido/fisiología , Plasticidad Neuronal/fisiología , Receptores AMPA/metabolismo , Animales , Espinas Dendríticas/efectos de los fármacos , Técnicas de Silenciamiento del Gen/métodos , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Autoadministración , Síndrome de Abstinencia a Sustancias/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
Positive, prosocial interactions are essential for survival, development, and well-being. These intricate and complex behaviors are mediated by an amalgamation of neural circuit mechanisms working in concert. Impairments in prosocial behaviors, which occur in a large number of neuropsychiatric disorders, result from disruption of the coordinated activity of these neural circuits. In this review, we focus our discussion on recent findings that utilize modern approaches in rodents to map, monitor, and manipulate neural circuits implicated in a variety of prosocial behaviors. We highlight how modulation by oxytocin, serotonin, and dopamine of excitatory and inhibitory synaptic transmission in specific brain regions is critical for regulation of adaptive prosocial interactions. We then describe how recent findings have helped elucidate pathophysiological mechanisms underlying the social deficits that accompany neuropsychiatric disorders. We conclude by discussing approaches for the development of more efficacious and targeted therapeutic interventions to ameliorate aberrant prosocial behaviors.
Asunto(s)
Altruismo , Oxitocina , Oxitocina/fisiología , Transmisión Sináptica , Encéfalo/fisiología , Dopamina , Conducta SocialRESUMEN
The neurobiological underpinnings of mood and anxiety disorders have been linked to the nucleus accumbens (NAc), a region important in processing the rewarding and emotional salience of stimuli. Using chronic social defeat stress, an animal model of mood and anxiety disorders, we investigated whether alterations in synaptic plasticity are responsible for the long-lasting behavioral symptoms induced by this form of stress. We hypothesized that chronic social defeat stress alters synaptic strength or connectivity of medium spiny neurons (MSNs) in the NAc to induce social avoidance. To test this, we analyzed the synaptic profile of MSNs via confocal imaging of Lucifer-yellow-filled cells, ultrastructural analysis of the postsynaptic density, and electrophysiological recordings of miniature EPSCs (mEPSCs) in mice after social defeat. We found that NAc MSNs have more stubby spine structures with smaller postsynaptic densities and an increase in the frequency of mEPSCs after social defeat. In parallel to these structural changes, we observed significant increases in IκB kinase (IKK) in the NAc after social defeat, a molecular pathway that has been shown to regulate neuronal morphology. Indeed, we find using viral-mediated gene transfer of dominant-negative and constitutively active IKK mutants that activation of IKK signaling pathways during social defeat is both necessary and sufficient to induce synaptic alterations and behavioral effects of the stress. These studies establish a causal role for IKK in regulating stress-induced adaptive plasticity and may present a novel target for drug development in the treatment of mood and anxiety disorders in humans.
Asunto(s)
Quinasa I-kappa B/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/patología , Núcleo Accumbens/patología , Estrés Psicológico/patología , Análisis de Varianza , Animales , Conducta Animal , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/genética , Conducta Exploratoria/fisiología , Regulación Enzimológica de la Expresión Génica/fisiología , Técnicas de Transferencia de Gen , Proteínas Fluorescentes Verdes/genética , Quinasa I-kappa B/genética , Relaciones Interpersonales , Isoquinolinas , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal/métodos , Microscopía Electrónica de Transmisión/métodos , Mutación/genética , Neuronas/fisiología , Neuronas/ultraestructura , Técnicas de Placa-Clamp , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Estadística como Asunto , Estrés Psicológico/fisiopatologíaRESUMEN
Abstract Stress can have a lasting impact on the structure and function of brain circuitry that results in long-lasting changes in the behavior of an organism. Synaptic plasticity is the mechanism by which information is stored and maintained within individual synapses, neurons, and neuronal circuits to guide the behavior of an organism. Although these mechanisms allow the organism to adapt to its constantly evolving environment, not all of these adaptations are beneficial. Under prolonged bouts of physical or psychological stress, these mechanisms become dysregulated, and the connectivity between brain regions becomes unbalanced, resulting in pathological behaviors. In this review, we highlight the effects of stress on the structure and function of neurons within the mesocorticolimbic brain systems known to regulate mood and motivation. We then discuss the implications of these spine adaptations on neuronal activity and pathological behaviors implicated in mood disorders. Finally, we end by discussing recent brain imaging studies in human depression within the context of these basic findings to provide insight into the underlying mechanisms leading to neural dysfunction in depression.
Asunto(s)
Encéfalo/patología , Encéfalo/fisiopatología , Plasticidad Neuronal/fisiología , Estrés Psicológico/patología , Sinapsis/patología , Animales , HumanosRESUMEN
Prosocial behaviors are essential for group cooperation, which enrich life experience and enhance survival. These complex behaviors are governed by intricate interactions between numerous neural circuits functioning in concert. Impairments in prosocial interactions result from disruptions of this coordinated brain activity and are a prominent feature of several pathological conditions including autism spectrum disorder, depression and addiction. Here we highlight recent studies that use advanced techniques to anatomically map, monitor and manipulate neural circuits that influence prosocial behavior. These recent findings provide important clues to unravel the complexities of the neural mechanisms that mediate prosocial interactions and offer insights into new strategies for the treatment of aberrant social behavior.
Asunto(s)
Altruismo , Trastorno del Espectro Autista , Humanos , Conducta SocialRESUMEN
Autism spectrum disorder (ASD) is a common set of heterogeneous neurodevelopmental disorders resulting from a variety of genetic and environmental risk factors. A core feature of ASD is impairment in prosocial interactions. Current treatment options for individuals diagnosed with ASD are limited, with no current FDA-approved medications that effectively treat its core symptoms. We recently demonstrated that enhanced serotonin (5-HT) activity in the nucleus accumbens (NAc), via optogenetic activation of 5-HTergic inputs or direct infusion of a specific 5-HT1b receptor agonist, reverses social deficits in a genetic mouse model for ASD based on 16p11.2 copy number variation. Furthermore, the recreational drug MDMA, which is currently being evaluated in clinical trials, promotes sociability in mice due to its 5-HT releasing properties in the NAc. Here, we systematically evaluated the ability of MDMA and a selective 5-HT1b receptor agonist to rescue sociability deficits in multiple different mouse models for ASD. We find that MDMA administration enhances sociability in control mice and reverses sociability deficits in all four ASD mouse models examined, whereas administration of a 5-HT1b receptor agonist selectively rescued the sociability deficits in all six mouse models for ASD. These preclinical findings suggest that pharmacological enhancement of 5-HT release or direct 5-HT1b receptor activation may be therapeutically efficacious in ameliorating some of the core sociability deficits present across etiologically distinct presentations of ASD.
Asunto(s)
Trastorno del Espectro Autista , Animales , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/genética , Variaciones en el Número de Copia de ADN , Modelos Animales de Enfermedad , Ratones , Serotonina , Conducta SocialRESUMEN
Hedonic feeding is driven by the "pleasure" derived from consuming palatable food and occurs in the absence of metabolic need. It plays a critical role in the excessive feeding that underlies obesity. Compared to other pathological motivated behaviors, little is known about the neural circuit mechanisms mediating excessive hedonic feeding. Here, we show that modulation of prefrontal cortex (PFC) and anterior paraventricular thalamus (aPVT) excitatory inputs to the nucleus accumbens (NAc), a key node of reward circuitry, has opposing effects on high fat intake in mice. Prolonged high fat intake leads to input- and cell type-specific changes in synaptic strength. Modifying synaptic strength via plasticity protocols, either in an input-specific optogenetic or non-specific electrical manner, causes sustained changes in high fat intake. These results demonstrate that input-specific NAc circuit adaptations occur with repeated exposure to a potent natural reward and suggest that neuromodulatory interventions may be therapeutically useful for individuals with pathologic hedonic feeding.
Asunto(s)
Ingestión de Alimentos/psicología , Conducta Alimentaria/psicología , Núcleo Accumbens/fisiología , Recompensa , Alimentación Animal , Animales , Grasas de la Dieta/administración & dosificación , Masculino , Ratones , Ratones Transgénicos , Microscopía Confocal , Núcleos Talámicos de la Línea Media/fisiología , Modelos Animales , Motivación , Vías Nerviosas/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Núcleo Accumbens/citología , Optogenética , Técnicas de Placa-Clamp , Corteza Prefrontal/fisiología , Técnicas Estereotáxicas , Proteína 2 de Transporte Vesicular de Glutamato/genéticaRESUMEN
Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK). To functionally interrogate BNSTâLH circuitry, we used tools for monitoring and manipulating neural activity with cell-type-specific resolution in freely behaving mice. We found that Crf-BNST and Cck-BNST neurons respectively provide abundant and sparse inputs onto Hcrt-LH neurons, display discrete physiological responses to salient stimuli, drive opposite emotionally valenced behaviors, and receive different proportions of inputs from upstream networks. Together, our data provide an advanced model for how parallel BNSTâLH pathways promote divergent emotional states via connectivity patterns of genetically defined, circuit-specific neuronal subpopulations.
Asunto(s)
Emociones/fisiología , Área Hipotalámica Lateral/fisiología , Vías Nerviosas/fisiología , Núcleos Septales/fisiología , Animales , Colecistoquinina/fisiología , Condicionamiento Operante/fisiología , Área Hipotalámica Lateral/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/citología , Red Nerviosa/fisiología , Vías Nerviosas/citología , Neuronas/fisiología , Neuropéptidos/metabolismo , Orexinas/metabolismo , Orexinas/fisiología , Estimulación Luminosa , Autoestimulación , Núcleos Septales/citología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
While the brain vasculature can be imaged with many methods, immunohistochemistry has distinct advantages due to its simplicity and applicability to archival tissue. However, immunohistochemical staining of the murine brain vasculature in aldehyde fixed tissue has proven elusive and inconsistent using current protocols. Here we investigated whether antigen retrieval methods could improve vascular staining in the adult mouse brain. We found that pepsin digestion prior to immunostaining unmasked widespread collagen IV staining of the cerebrovasculature in the adult mouse brain. Pepsin treatment also unmasked widespread vascular staining with laminin, but only marginally improved isolectin B4 staining and did not enhance vascular staining with fibronectin, perlecan or CD146. Collagen IV immunoperoxidase staining was easily combined with cresyl violet counterstaining making it suitable for stereological analyses of both vascular and neuronal parameters in the same tissue section. This method should be widely applicable for labeling the brain vasculature of the mouse in aldehyde fixed tissue from both normal and pathological states.
Asunto(s)
Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/metabolismo , Encéfalo/anatomía & histología , Colágeno Tipo IV/metabolismo , Fármacos Gastrointestinales/farmacología , Pepsina A/farmacología , Animales , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica/métodos , Indoles , Laminina/metabolismo , Lectinas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.