RESUMO
Historically associated with aversion, the lateral habenula has a poorly characterized role in parenting. In this issue of Neuron, Lecca and colleagues1 show that these seemingly opposing roles converge in a subnucleus where aversion to pup cries may drive motivation for caregiving.
Assuntos
Choro , Habenula , Humanos , Lactente , Choro/fisiologia , Poder Familiar , Afeto , MotivaçãoRESUMO
Infant avoidance and aggression are promoted by activation of the Urocortin-3 expressing neurons of the perifornical area of hypothalamus (PeFAUcn3) in male and female mice. PeFAUcn3 neurons have been implicated in stress, and stress is known to reduce maternal behavior. We asked how chronic restraint stress (CRS) affects infant-directed behavior in virgin and lactating females and what role PeFAUcn3 neurons play in this process. Here we show that infant-directed behavior increases activity in the PeFAUcn3 neurons in virgin and lactating females. Chemogenetic inhibition of PeFAUcn3 neurons facilitates pup retrieval in virgin females. CRS reduces pup retrieval in virgin females and increases activity of PeFAUcn3 neurons, while CRS does not affect maternal behavior in lactating females. Inhibition of PeFAUcn3 neurons blocks stress-induced deficits in pup-directed behavior in virgin females. Together, these data illustrate the critical role for PeFAUcn3 neuronal activity in mediating the impact of chronic stress on female infant-directed behavior.
Assuntos
Lactação , Urocortinas , Animais , Feminino , Masculino , Camundongos , Agressão , Hipotálamo , Comportamento Materno , NeurôniosRESUMO
Depression is a prevalent mental health disorder and is the number one cause of disability worldwide. Risk factors for depression include genetic predisposition and stressful life events, and depression is twice as prevalent in women compared to men. Both clinical and preclinical research have implicated a critical role for brain-derived neurotrophic factor (BDNF) signaling in depression pathology as well as therapeutics. A preponderance of this research has focused on the role of BDNF and its primary receptor tropomyosin-related kinase B (TrkB) in the cortex and hippocampus. However, much of the symptomatology for depression is consistent with disruptions in functions of the hypothalamus including changes in weight, activity levels, responses to stress, and sociability. Here, we review evidence for the role of BDNF and TrkB signaling in the regions of the hypothalamus and their role in these autonomic and behavioral functions associated with depression. In addition, we identify areas for further research. Understanding the role of BDNF signaling in the hypothalamus will lead to valuable insights for sex- and stress-dependent neurobiological underpinnings of depression pathology.
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The amygdalohippocampal transition area (AHi) has emerged as a critical nucleus of sociosexual behaviors such as mating, parenting, and aggression. The AHi has been overlooked in rodent and human amygdala studies until recently. The AHi is hypothesized to play a role in metabolic and cognitive functions as well as social behaviors based on its connectivity and molecular composition. The AHi is small nucleus rich in neuropeptide and hormone receptors and is contiguous with the ventral subiculum of the hippocampus-hence its designation as a "transition area". Literature focused on the AHi can be difficult to interpret because of changing nomenclature and conflation with neighboring nuclei. Here we summarize what is currently known about AHi structure and development, connections throughout the brain, molecular composition, and functional significance. We aim to delineate current knowledge regarding the AHi, identify potential functions with supporting evidence, and ultimately make clear the importance of the AHi in sociosexual function.
Assuntos
Tonsila do Cerebelo , Hipocampo , Humanos , Tonsila do Cerebelo/fisiologia , Hipocampo/fisiologia , Mapeamento Encefálico , Encéfalo , Comportamento SocialAssuntos
Evolução Biológica , Comportamento Social , Animais , Comportamento Animal , Criança , Humanos , Cuidado do Lactente , PaisRESUMO
Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes. In model systems, ketamine appears to display a combination of neurotoxic and neuroprotective properties that are context dependent. At anesthetic doses applied during neurodevelopmental windows, ketamine contributes to inflammation, autophagy, apoptosis, and enhances levels of reactive oxygen species. At the same time, subanesthetic dose ketamine is a powerful activator of multiple parallel neurotrophic signaling cascades with neuroprotective actions that are not always NMDAR-dependent. Here, we summarize results from an array of preclinical studies that highlight a complex landscape of intracellular signaling pathways modulated by ketamine and juxtapose the somewhat contrasting neuroprotective and neurotoxic features of this drug.
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While recent studies have uncovered dedicated neural pathways mediating the positive control of parenting, the regulation of infant-directed aggression and how it relates to adult-adult aggression is poorly understood. Here we show that urocortin-3 (Ucn3)-expressing neurons in the hypothalamic perifornical area (PeFAUcn3) are activated during infant-directed attacks in males and females, but not other behaviors. Functional manipulations of PeFAUcn3 neurons demonstrate the role of this population in the negative control of parenting in both sexes. PeFAUcn3 neurons receive input from areas associated with vomeronasal sensing, stress, and parenting, and send projections to hypothalamic and limbic areas. Optogenetic activation of PeFAUcn3 axon terminals in these regions triggers various aspects of infant-directed agonistic responses, such as neglect, repulsion, and aggression. Thus, PeFAUcn3 neurons emerge as a dedicated circuit component controlling infant-directed neglect and aggression, providing a new framework to understand the positive and negative regulation of parenting in health and disease.
Assuntos
Agressão , Comportamento Animal , Hipotálamo/metabolismo , Comportamento Materno , Neurônios/metabolismo , Comportamento Paterno , Urocortinas/metabolismo , Animais , Feminino , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/metabolismo , Optogenética , Fatores Sexuais , Urocortinas/genéticaRESUMO
The rapidly acting antidepressants ketamine and scopolamine exert behavioral effects that can last from several days to more than a week in some patients. The molecular mechanisms underlying the maintenance of these antidepressant effects are unknown. Here we show that methyl-CpG-binding protein 2 (MeCP2) phosphorylation at Ser421 (pMeCP2) is essential for the sustained, but not the rapid, antidepressant effects of ketamine and scopolamine in mice. Our results reveal that pMeCP2 is downstream of BDNF, a critical factor in ketamine and scopolamine antidepressant action. In addition, we show that pMeCP2 is required for the long-term regulation of synaptic strength after ketamine or scopolamine administration. These results demonstrate that pMeCP2 and associated synaptic plasticity are essential determinants of sustained antidepressant effects.
Assuntos
Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Proteína 2 de Ligação a Metil-CpG/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Ketamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Fosforilação , Escopolamina/farmacologiaRESUMO
Parenting is essential for the survival and wellbeing of mammalian offspring. However, we lack a circuit-level understanding of how distinct components of this behaviour are coordinated. Here we investigate how galanin-expressing neurons in the medial preoptic area (MPOAGal) of the hypothalamus coordinate motor, motivational, hormonal and social aspects of parenting in mice. These neurons integrate inputs from a large number of brain areas and the activation of these inputs depends on the animal's sex and reproductive state. Subsets of MPOAGal neurons form discrete pools that are defined by their projection sites. While the MPOAGal population is active during all episodes of parental behaviour, individual pools are tuned to characteristic aspects of parenting. Optogenetic manipulation of MPOAGal projections mirrors this specificity, affecting discrete parenting components. This functional organization, reminiscent of the control of motor sequences by pools of spinal cord neurons, provides a new model for how discrete elements of a social behaviour are generated at the circuit level.
Assuntos
Comportamento Materno/fisiologia , Comportamento Materno/psicologia , Vias Neurais , Comportamento Paterno/fisiologia , Comportamento Paterno/psicologia , Comportamento Social , Animais , Feminino , Galanina/metabolismo , Hormônios/metabolismo , Lógica , Masculino , Camundongos , Motivação , Neurônios/metabolismo , Optogenética , Poder Familiar , Área Pré-Óptica/citologia , Área Pré-Óptica/fisiologia , Reprodução/fisiologia , Caracteres SexuaisRESUMO
Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB), have important roles in neural plasticity and are required for antidepressant efficacy. Studies examining the role of BDNF-TrkB signaling in depression and antidepressant efficacy have largely focused on the limbic system, leaving it unclear whether this signaling is important in other brain regions. BDNF and TrkB are both highly expressed in the dorsal raphe nucleus (DRN), a brain region that has been suggested to have a role in depression and antidepressant action, although it is unknown whether BDNF and TrkB in the dorsal raphe nucleus are involved in these processes. We combined the adeno-associated virus (AAV) with the Cre-loxP site-specific recombination system to selectively knock down either Bdnf or TrkB in the DRN. These mice were then characterized in several behavioral paradigms including measures of depression-related behavior and antidepressant efficacy. We show that knockdown of TrkB, but not Bdnf, in the DRN results in loss of antidepressant efficacy and increased aggression-related behavior. We also show that knockdown of TrkB or Bdnf in this brain region does not have an impact on weight, activity levels, anxiety, or depression-related behaviors. These data reveal a critical role for TrkB signaling in the DRN in mediating antidepressant responses and normal aggression behavior. The results also suggest a non-cell autonomous role for BDNF in the DRN in mediating antidepressant efficacy.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Receptor trkB/metabolismo , Transdução de Sinais , Animais , Animais Geneticamente Modificados , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/deficiência , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Núcleo Dorsal da Rafe/efeitos dos fármacos , Masculino , Camundongos , Receptor trkB/deficiênciaRESUMO
Social interactions are essential for animals to reproduce, defend their territory, and raise their young. The conserved nature of social behaviors across animal species suggests that the neural pathways underlying the motivation for, and the execution of, specific social responses are also maintained. Modern tools of neuroscience have offered new opportunities for dissecting the molecular and neural mechanisms controlling specific social responses. We will review here recent insights into the neural circuits underlying a particularly fascinating and important form of social interaction, that of parental care. We will discuss how these findings open new avenues to deconstruct infant-directed behavioral control in males and females, and to help understand the neural basis of parenting in a variety of animal species, including humans. Please also see the video abstract here.
Assuntos
Encéfalo/fisiologia , Mamíferos/fisiologia , Motivação , Vias Neurais/fisiologia , Poder Familiar/psicologia , Animais , Feminino , Humanos , Masculino , Mamíferos/psicologia , Comportamento Materno/fisiologia , Comportamento Materno/psicologia , Comportamento Paterno/fisiologia , Comportamento Paterno/psicologiaRESUMO
DNA methylation has been shown to impact certain forms of synaptic and behavioral plasticity that have been implicated in the development in psychiatric disorders. DNA methylation is catalyzed by DNA methyltransferase (DNMT) enzymes that continue to be expressed in postmitotic neurons in the forebrain. Using a conditional forebrain knockout of DNMT1 or DNMT3a we assessed the role of these DNMTs in anxiety and depressive-like behavior in mice using an array of behavioral testing paradigms. Forebrain deletion of DNMT1 had anxiolytic and antidepressant-like properties as assessed by elevated plus maze, novelty suppressed feeding, forced swim, and social interaction tests. DNMT3a knockout mice, by contrast, did not exhibit significant behavioral alterations in these tests. Given the putative role of altered DNA methylation patterns in the development of schizophrenia, we also assessed DNMT1 and DNMT3a knockout mice in a prepulse inhibition task and found an enhanced prepulse inhibition of startle in DNMT1 knockouts relative to wild type mice, with no change evident in DNMT3a knockout mice. Our data suggest that DNMT1 and DNMT3a are distinctly involved in affective behavior and that DNMT1 may ultimately represent a potential target for treatment of certain affective behavioral disorders.
Assuntos
Ansiedade , Comportamento Animal/fisiologia , DNA (Citosina-5-)-Metiltransferase 1/fisiologia , DNA (Citosina-5-)-Metiltransferases/fisiologia , Depressão , Inibição Pré-Pulso , Prosencéfalo/metabolismo , Animais , Ansiedade/genética , Ansiedade/fisiopatologia , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Depressão/genética , Depressão/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibição Pré-Pulso/genética , Inibição Pré-Pulso/fisiologiaRESUMO
Understanding how neural information is processed in physiological and pathological states would benefit from precise detection, localization, and quantification of the activity of all neurons across the entire brain, which has not, to date, been achieved in the mammalian brain. We introduce a pipeline for high-speed acquisition of brain activity at cellular resolution through profiling immediate early gene expression using immunostaining and light-sheet fluorescence imaging, followed by automated mapping and analysis of activity by an open-source software program we term ClearMap. We validate the pipeline first by analysis of brain regions activated in response to haloperidol. Next, we report new cortical regions downstream of whisker-evoked sensory processing during active exploration. Last, we combine activity mapping with axon tracing to uncover new brain regions differentially activated during parenting behavior. This pipeline is widely applicable to different experimental paradigms, including animal species for which transgenic activity reporters are not readily available.
Assuntos
Comportamento Animal , Imuno-Histoquímica , Neuroimagem/métodos , Animais , Antipsicóticos/administração & dosagem , Encéfalo/metabolismo , Comportamento Exploratório , Genes Precoces , Haloperidol/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Ketamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDAR activation at rest, which inhibits eukaryotic elongation factor 2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from adult animals. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDARs is sufficient to trigger this effect. These findings suggest that global blockade of NMDARs in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.
RESUMO
Mice display robust, stereotyped behaviours towards pups: virgin males typically attack pups, whereas virgin females and sexually experienced males and females display parental care. Here we show that virgin males genetically impaired in vomeronasal sensing do not attack pups and are parental. Furthermore, we uncover a subset of galanin-expressing neurons in the medial preoptic area (MPOA) that are specifically activated during male and female parenting, and a different subpopulation that is activated during mating. Genetic ablation of MPOA galanin neurons results in marked impairment of parental responses in males and females and affects male mating. Optogenetic activation of these neurons in virgin males suppresses inter-male and pup-directed aggression and induces pup grooming. Thus, MPOA galanin neurons emerge as an essential regulatory node of male and female parenting behaviour and other social responses. These results provide an entry point to a circuit-level dissection of parental behaviour and its modulation by social experience.
Assuntos
Galanina/metabolismo , Comportamento Materno/fisiologia , Neurônios/metabolismo , Comportamento Paterno/fisiologia , Área Pré-Óptica/citologia , Agressão/fisiologia , Animais , Copulação , Feminino , Galanina/deficiência , Galanina/genética , Asseio Animal/fisiologia , Masculino , Camundongos , Optogenética , Feromônios/análise , Área Pré-Óptica/metabolismo , Canais de Cátion TRPC/deficiência , Canais de Cátion TRPC/genética , Órgão Vomeronasal/fisiologiaRESUMO
The impact of spontaneous neurotransmission on neuronal plasticity remains poorly understood. Here, we show that acute suppression of spontaneous NMDA receptor-mediated (NMDAR-mediated) neurotransmission potentiates synaptic responses in the CA1 regions of rat and mouse hippocampus. This potentiation requires protein synthesis, brain-derived neurotrophic factor expression, eukaryotic elongation factor-2 kinase function, and increased surface expression of AMPA receptors. Our behavioral studies link this same synaptic signaling pathway to the fast-acting antidepressant responses elicited by ketamine. We also show that selective neurotransmitter depletion from spontaneously recycling vesicles triggers synaptic potentiation via the same pathway as NMDAR blockade, demonstrating that presynaptic impairment of spontaneous release, without manipulation of evoked neurotransmission, is sufficient to elicit postsynaptic plasticity. These findings uncover an unexpectedly dynamic impact of spontaneous glutamate release on synaptic efficacy and provide new insight into a key synaptic substrate for rapid antidepressant action.
Assuntos
Hipocampo/citologia , Inibição Psicológica , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Análise de Variância , Animais , Animais Recém-Nascidos , Biofísica , Fator Neurotrófico Derivado do Encéfalo/deficiência , Estimulação Elétrica , Quinase do Fator 2 de Elongação/deficiência , Inibidores Enzimáticos/farmacologia , Potenciais Evocados/genética , Potenciais Evocados/fisiologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Antagonistas GABAérgicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Ácido Glutâmico/metabolismo , Hipocampo/fisiologia , Técnicas In Vitro , Ketamina/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/genética , Camundongos , Camundongos Knockout , Inibição Neural/efeitos dos fármacos , Técnicas de Patch-Clamp , Picrotoxina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Natação/fisiologia , Tetrodotoxina/farmacologia , Fatores de TempoRESUMO
Exposure to stress and hallucinogens in adulthood evokes persistent alterations in neurocircuitry and emotional behaviour. The structural and functional changes induced by stress and hallucinogen exposure are thought to involve transcriptional alterations in specific effector immediate early genes. The immediate early gene, activity regulated cytoskeletal-associated protein (Arc), is important for both activity and experience dependent plasticity. We sought to examine whether trophic factor signalling through brain-derived neurotrophic factor (BDNF) contributes to the neocortical regulation of Arc mRNA in response to distinct stimuli such as immobilization stress and the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI). Acute exposure to either immobilization stress or DOI induced Arc mRNA levels within the neocortex. BDNF infusion into the neocortex led to a robust up-regulation of local Arc transcript expression. Further, baseline Arc mRNA expression in the neocortex was significantly decreased in inducible BDNF knockout mice with an adult-onset, forebrain specific BDNF loss. The induction of Arc mRNA levels in response to both acute immobilization stress or a single administration of DOI was significantly attenuated in the inducible BDNF knockout mice. Taken together, our results implicate trophic factor signalling through BDNF in the regulation of cortical Arc mRNA expression, both under baseline conditions and following stress and hallucinogen exposure. These findings suggest the possibility that the regulation of Arc expression via BDNF provides a molecular substrate for the structural and synaptic plasticity observed following stimuli such as stress and hallucinogens.
Assuntos
Anfetaminas/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Alucinógenos/farmacologia , Proteínas Musculares/metabolismo , Estresse Psicológico/metabolismo , Regulação para Cima/efeitos dos fármacos , Análise de Variância , Animais , Proteínas Reguladoras de Apoptose/genética , Infarto Encefálico/etiologia , Infarto Encefálico/metabolismo , Fator Neurotrófico Derivado do Encéfalo/deficiência , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Regulação para Cima/genéticaRESUMO
Rett syndrome and MECP2 duplication syndrome are neurodevelopmental disorders that arise from loss-of-function and gain-of-function alterations in methyl-CpG binding protein 2 (MeCP2) expression, respectively. Although there have been studies examining MeCP2 loss of function in animal models, there is limited information on MeCP2 overexpression in animal models. Here, we characterize a mouse line with MeCP2 overexpression restricted to neurons (Tau-Mecp2). This MeCP2 overexpression line shows motor coordination deficits, heightened anxiety, and impairments in learning and memory that are accompanied by deficits in long-term potentiation and short-term synaptic plasticity. Whole-cell voltage-clamp recordings of cultured hippocampal neurons from Tau-Mecp2 mice reveal augmented frequency of miniature EPSCs with no change in miniature IPSCs, indicating that overexpression of MeCP2 selectively impacts excitatory synapse function. Moreover, we show that alterations in transcriptional repression mechanisms underlie the synaptic phenotypes in hippocampal neurons from the Tau-Mecp2 mice. These results demonstrate that the Tau-Mecp2 mouse line recapitulates many key phenotypes of MECP2 duplication syndrome and support the use of these mice to further study this devastating disorder.