RESUMO
Physical or mental stress leads to neuroplasticity in the brain and increases the risk of depression and anxiety. Stress exposure causes the dysfunction of peripheral T lymphocytes. However, the pathological role and underlying regulatory mechanism of peripheral T lymphocytes in mood disorders have not been well established. Here, we show that the lack of CD4+ T cells protects mice from stress-induced anxiety-like behavior. Physical stress-induced leukotriene B4 triggers severe mitochondrial fission in CD4+ T cells, which further leads to a variety of behavioral abnormalities including anxiety, depression, and social disorders. Metabolomic profiles and single-cell transcriptome reveal that CD4+ T cell-derived xanthine acts on oligodendrocytes in the left amygdala via adenosine receptor A1. Mitochondrial fission promotes the de novo synthesis of purine via interferon regulatory factor 1 accumulation in CD4+ T cells. Our study implicates a critical link between a purine metabolic disorder in CD4+ T cells and stress-driven anxiety-like behavior.
Assuntos
Ansiedade/metabolismo , Comportamento Animal/fisiologia , Encefalopatias Metabólicas/metabolismo , Estresse Psicológico/metabolismo , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Animais , Ansiedade/genética , Ansiedade/imunologia , Ansiedade/fisiopatologia , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/fisiopatologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Dinâmica Mitocondrial/genética , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Análise de Célula Única , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Transcriptoma/genética , Xantina/metabolismoRESUMO
Human brain networks that encode variation in mood on naturalistic timescales remain largely unexplored. Here we combine multi-site, semi-chronic, intracranial electroencephalography recordings from the human limbic system with machine learning methods to discover a brain subnetwork that correlates with variation in individual subjects' self-reported mood over days. First we defined the subnetworks that influence intrinsic brain dynamics by identifying regions that showed coordinated changes in spectral coherence. The most common subnetwork, found in 13 of 21 subjects, was characterized by ß-frequency coherence (13-30 Hz) between the amygdala and hippocampus. Increased variability of this subnetwork correlated with worsening mood across these 13 subjects. Moreover, these subjects had significantly higher trait anxiety than the 8 of 21 for whom this amygdala-hippocampus subnetwork was absent. These results demonstrate an approach for extracting network-behavior relationships from complex datasets, and they reveal a conserved subnetwork associated with a psychological trait that significantly influences intrinsic brain dynamics and encodes fluctuations in mood.
Assuntos
Afeto , Tonsila do Cerebelo/fisiopatologia , Ansiedade/fisiopatologia , Hipocampo/fisiopatologia , Rede Nervosa/fisiopatologia , Adulto , Eletroencefalografia , Feminino , Humanos , Aprendizado de Máquina , Masculino , Processamento de Sinais Assistido por ComputadorRESUMO
The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.
Assuntos
Núcleo Dorsal da Rafe/anatomia & histologia , Núcleo Dorsal da Rafe/fisiologia , Serotonina/fisiologia , Adaptação Psicológica/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Ansiedade/fisiopatologia , Encéfalo/fisiologia , Núcleo Dorsal da Rafe/metabolismo , Feminino , Lobo Frontal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Serotonina/metabolismoRESUMO
T cells reorganize their metabolic profiles after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. Here we report that augmented T cell responses in Pdcd1-/- mice, which lack the inhibitory receptor PD-1, induced a metabolic serum signature characterized by depletion of amino acids. We found that the depletion of amino acids in serum was due to the accumulation of amino acids in activated Pdcd1-/- T cells in the lymph nodes. A systemic decrease in tryptophan and tyrosine led to substantial deficiency in the neurotransmitters serotonin and dopamine in the brain, which resulted in behavioral changes dominated by anxiety-like behavior and exacerbated fear responses. Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system.
Assuntos
Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Medo/fisiologia , Ativação Linfocitária/imunologia , Receptor de Morte Celular Programada 1/genética , Linfócitos T/imunologia , Aminoácidos/sangue , Animais , Encéfalo/metabolismo , Dopamina/deficiência , Interferon gama/sangue , Cinurenina/sangue , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1/deficiência , Serotonina/deficiência , Linfócitos T/metabolismo , Triptofano/metabolismo , Tirosina/metabolismoRESUMO
The extended amygdala has dominated research on the neural circuitry of fear and anxiety, but the septohippocampal axis also plays an important role. The lateral septum (LS) is thought to suppress fear and anxiety through its outputs to the hypothalamus. However, this structure has not yet been dissected using modern tools. The type 2 CRF receptor (Crfr2) marks a subset of LS neurons whose functional connectivity we have investigated using optogenetics. Crfr2(+) cells include GABAergic projection neurons that connect with the anterior hypothalamus. Surprisingly, we find that these LS outputs enhance stress-induced behavioral measures of anxiety. Furthermore, transient activation of Crfr2(+) neurons promotes, while inhibition suppresses, persistent anxious behaviors. LS Crfr2(+) outputs also positively regulate circulating corticosteroid levels. These data identify a subset of LS projection neurons that promote, rather than suppress, stress-induced behavioral and endocrinological dimensions of persistent anxiety states and provide a cellular point of entry to LS circuitry.
Assuntos
Ansiedade/fisiopatologia , Hipotálamo/metabolismo , Septo do Cérebro/fisiologia , Corticosteroides/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/fisiologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Estresse FisiológicoRESUMO
Emotional states influence bodily physiology, as exemplified in the top-down process by which anxiety causes faster beating of the heart1-3. However, whether an increased heart rate might itself induce anxiety or fear responses is unclear3-8. Physiological theories of emotion, proposed over a century ago, have considered that in general, there could be an important and even dominant flow of information from the body to the brain9. Here, to formally test this idea, we developed a noninvasive optogenetic pacemaker for precise, cell-type-specific control of cardiac rhythms of up to 900 beats per minute in freely moving mice, enabled by a wearable micro-LED harness and the systemic viral delivery of a potent pump-like channelrhodopsin. We found that optically evoked tachycardia potently enhanced anxiety-like behaviour, but crucially only in risky contexts, indicating that both central (brain) and peripheral (body) processes may be involved in the development of emotional states. To identify potential mechanisms, we used whole-brain activity screening and electrophysiology to find brain regions that were activated by imposed cardiac rhythms. We identified the posterior insular cortex as a potential mediator of bottom-up cardiac interoceptive processing, and found that optogenetic inhibition of this brain region attenuated the anxiety-like behaviour that was induced by optical cardiac pacing. Together, these findings reveal that cells of both the body and the brain must be considered together to understand the origins of emotional or affective states. More broadly, our results define a generalizable approach for noninvasive, temporally precise functional investigations of joint organism-wide interactions among targeted cells during behaviour.
Assuntos
Comportamento Animal , Encéfalo , Emoções , Coração , Animais , Camundongos , Ansiedade/fisiopatologia , Encéfalo/fisiologia , Mapeamento Encefálico , Emoções/fisiologia , Coração/fisiologia , Comportamento Animal/fisiologia , Eletrofisiologia , Optogenética , Córtex Insular/fisiologia , Frequência Cardíaca , Channelrhodopsins , Taquicardia/fisiopatologia , Marca-Passo ArtificialRESUMO
Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain1. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved2. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men1. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium3-5. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings3,6 but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation7,8. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell-mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell-mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain.
Assuntos
Ansiedade , Células Enterocromafins , Dor Visceral , Feminino , Humanos , Masculino , Ansiedade/complicações , Ansiedade/fisiopatologia , Sistema Digestório/inervação , Sistema Digestório/fisiopatologia , Células Enterocromafins/metabolismo , Síndrome do Intestino Irritável/complicações , Síndrome do Intestino Irritável/fisiopatologia , Síndrome do Intestino Irritável/psicologia , Caracteres Sexuais , Dor Visceral/complicações , Dor Visceral/fisiopatologia , Dor Visceral/psicologia , Inflamação/complicações , Inflamação/fisiopatologia , Serotonina/metabolismo , Reprodutibilidade dos TestesRESUMO
Magnetic fields pass through tissue undiminished and without producing harmful effects, motivating their use as a wireless, minimally invasive means to control neural activity. Here, we review mechanisms and techniques coupling magnetic fields to changes in electrochemical potentials across neuronal membranes. Biological magnetoreception, although incompletely understood, is discussed as a potential source of inspiration. The emergence of magnetic properties in materials is reviewed to clarify the distinction between biomolecules containing transition metals and ferrite nanoparticles that exhibit significant net moments. We describe recent developments in the use of magnetic nanomaterials as transducers converting magnetic stimuli to forms readily perceived by neurons and discuss opportunities for multiplexed and bidirectional control as well as the challenges posed by delivery to the brain. The variety of magnetic field conditions and mechanisms by which they can be coupled to neuronal signaling cascades highlights the desirability of continued interchange between magnetism physics and neurobiology.
Assuntos
Comportamento Animal/fisiologia , Encéfalo/fisiologia , Campos Magnéticos , Rede Nervosa/fisiologia , Animais , Ansiedade/fisiopatologia , Humanos , Neurônios/fisiologiaRESUMO
Trait anxiety is a major risk factor for stress-induced and anxiety disorders in humans. However, animal models accounting for the interindividual variability in stress vulnerability are largely lacking. Moreover, the pervasive bias of using mostly male animals in preclinical studies poorly reflects the increased prevalence of psychiatric disorders in women. Using the threat imminence continuum theory, we designed and validated an auditory aversive conditioning-based pipeline in both female and male mice. We operationalised trait anxiety by harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy. While sustained freezing during prolonged retrieval sessions was identified as an anxiety-endophenotype behavioral marker in both sexes, females were consistently associated with an increased freezing response. RNA-sequencing of CeA, BLA, ACC, and BNST revealed massive differences in phasic and sustained responders' transcriptomes, correlating with transcriptomic signatures of psychiatric disorders, particularly post-traumatic stress disorder (PTSD). Moreover, we detected significant alterations in the excitation/inhibition balance of principal neurons in the lateral amygdala. These findings provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility in a sex-specific manner.
Assuntos
Ansiedade , Modelos Animais de Doenças , Animais , Masculino , Feminino , Ansiedade/fisiopatologia , Ansiedade/genética , Camundongos , Medo/fisiologia , Camundongos Endogâmicos C57BL , Transtornos de Estresse Pós-Traumáticos/genética , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transcriptoma/genética , Tonsila do Cerebelo/metabolismo , Comportamento Animal/fisiologiaRESUMO
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is reported to be the most common type of autosomal dominant cerebellar ataxia (ADCA). SCA3 patients suffer from a progressive decline in motor coordination and other disease-associated symptoms. Moreover, recent studies have reported that SCA3 patients also exhibit symptoms of cerebellar cognitive affective syndrome (CCAS). We previously observed signs of CCAS in mouse model of SCA3. Particularly, SCA3-84Q mice suffer from anxiety, recognition memory decline, and also exhibit signs of low mood and aversion to activity. Here we studied the effect of long-term injections of SK channels activator chlorzoxazone (CHZ) together and separately with the folic acid (FA) on the cerebellar Purkinje cell (PC) firing and histology, and also on the motor and cognitive functions as well as mood alterations in SCA3-84Q hemizygous transgenic mice. We realized that both CHZ and CHZ-FA combination had similar positive effect on pure cerebellum impairments including PC firing precision, PC histology, and motor performance in SCA3-84Q mice. However, only the CHZ-FA combination, but not CHZ, had significantly ameliorated the signs of anxiety and depression, and also noticeably improved recognition memory in SCA3-84Q mice. Our results suggest that the combination therapy for both ataxia and non-motor symptoms is required for the complex treatment of ADCA.
Assuntos
Ansiedade , Clorzoxazona , Depressão , Modelos Animais de Doenças , Ácido Fólico , Doença de Machado-Joseph , Camundongos Transgênicos , Animais , Camundongos , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Depressão/tratamento farmacológico , Depressão/genética , Depressão/fisiopatologia , Ácido Fólico/farmacologia , Ácido Fólico/administração & dosagem , Doença de Machado-Joseph/tratamento farmacológico , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/fisiopatologia , Doença de Machado-Joseph/patologia , Clorzoxazona/farmacologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Memória/efeitos dos fármacos , Humanos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Masculino , Ataxina-3/genética , Ataxina-3/metabolismoRESUMO
Epidemiological sex differences in anxiety disorders and major depression are well characterized. Yet the circuits and mechanisms that contribute to these differences are understudied, because preclinical studies have historically excluded female rodents. This oversight is beginning to be addressed, and recent studies that include male and female rodents are identifying sex differences in neurobiological processes that underlie features of these disorders, including conflict anxiety, fear processing, arousal, social avoidance, learned helplessness and anhedonia. These findings allow us to conceptualize various types of sex differences in the brain, which in turn have broader implications for considering sex as a biological variable. Importantly, comparing the sexes could aid in the discovery of novel therapeutics.
Assuntos
Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Depressão/fisiopatologia , Rede Nervosa/fisiopatologia , Caracteres Sexuais , Animais , Ansiedade/diagnóstico , Ansiedade/psicologia , Depressão/diagnóstico , Depressão/psicologia , Feminino , Humanos , MasculinoRESUMO
Persistent neural activity in cortical, hippocampal, and motor networks has been described as mediating working memory for transiently encountered stimuli1,2. Internal emotional states, such as fear, also persist following exposure to an inciting stimulus3, but it is unclear whether slow neural dynamics are involved in this process. Neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) that express the nuclear receptor protein NR5A1 (also known as SF1) are necessary for defensive responses to predators in mice4-7. Optogenetic activation of these neurons, referred to here as VMHdmSF1 neurons, elicits defensive behaviours that outlast stimulation5,8, which suggests the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdmSF1 neurons in mice exhibit activity that lasts for many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behaviour in an open-field assay, and depended on neurotransmitter release from VMHdmSF1 neurons. Stimulation and calcium imaging in acute slices showed that there is local excitatory connectivity between VMHdmSF1 neurons. Microendoscopic calcium imaging of VMHdmSF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdmSF1 subpopulations were persistently activated by different modalities of threatening stimulus. Computational modelling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results show that stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that of working memory in the cortex9,10, contribute to a persistent emotional state.
Assuntos
Medo/fisiologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Neurônios/fisiologia , Estimulação Acústica , Animais , Ansiedade/fisiopatologia , Cálcio/análise , Simulação por Computador , Sinais (Psicologia) , Masculino , Camundongos , Neurotransmissores/metabolismo , Optogenética , Comportamento Predatório , Fatores de TempoRESUMO
Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signalling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioural abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis1-4. We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviours in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signalling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.
Assuntos
Encéfalo/crescimento & desenvolvimento , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Inflamassomos/metabolismo , Animais , Animais Recém-Nascidos , Ansiedade/patologia , Ansiedade/fisiopatologia , Ansiedade/psicologia , Comportamento Animal/fisiologia , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/deficiência , Caspase 1/metabolismo , Morte Celular , Proteínas de Ligação a DNA/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Proteínas de Ligação a Fosfato/metabolismoRESUMO
Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.
Assuntos
Antecipação Psicológica , Ansiedade , Imageamento por Ressonância Magnética , Humanos , Masculino , Feminino , Ansiedade/psicologia , Ansiedade/fisiopatologia , Adulto , Antecipação Psicológica/fisiologia , Adulto Jovem , Percepção da Dor/fisiologia , Dor/psicologia , Dor/fisiopatologia , Teorema de Bayes , Emoções/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Encéfalo/fisiologia , Prazer/fisiologia , Mapeamento EncefálicoRESUMO
Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.
Assuntos
Ansiedade , Vias Neurais , Córtex Pré-Frontal , Estresse Psicológico , Animais , Ansiedade/psicologia , Ansiedade/fisiopatologia , Masculino , Estresse Psicológico/psicologia , Estresse Psicológico/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Vias Neurais/fisiopatologia , Vias Neurais/fisiologia , Camundongos , Medo/fisiologia , Medo/psicologia , Camundongos Endogâmicos C57BL , Área Tegmentar Ventral/fisiopatologia , Tálamo/fisiopatologia , Núcleo Mediodorsal do Tálamo/fisiologia , Núcleo Mediodorsal do Tálamo/fisiopatologiaRESUMO
Neocortex expansion during human evolution provides a basis for our enhanced cognitive abilities. Yet, which genes implicated in neocortex expansion are actually responsible for higher cognitive abilities is unknown. The expression of human-specific ARHGAP11B in embryonic/foetal mouse, ferret and marmoset neocortex was previously found to promote basal progenitor proliferation, upper-layer neuron generation and neocortex expansion during development, features commonly thought to contribute to increased cognitive abilities. However, a key question is whether this phenotype persists into adulthood and if so, whether cognitive abilities are indeed increased. Here, we generated a transgenic mouse line with physiological ARHGAP11B expression that exhibits increased neocortical size and upper-layer neuron numbers persisting into adulthood. Adult ARHGAP11B-transgenic mice showed altered neurobehaviour, notably increased memory flexibility and a reduced anxiety level. Our data are consistent with the notion that neocortex expansion by ARHGAP11B, a gene implicated in human evolution, underlies some of the altered neurobehavioural features observed in the transgenic mice, such as the increased memory flexibility, a neocortex-associated trait, with implications for the increase in cognitive abilities during human evolution.
Assuntos
Proteínas Ativadoras de GTPase/metabolismo , Memória/fisiologia , Neocórtex/metabolismo , Neocórtex/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Animais , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Evolução Biológica , Proliferação de Células/fisiologia , Cognição/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/fisiologiaRESUMO
A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.
Assuntos
Ansiedade/psicologia , Ansiedade/terapia , Extinção Psicológica/fisiologia , Medo/fisiologia , Medo/psicologia , Vias Neurais/fisiologia , Colículos Superiores/citologia , Colículos Superiores/fisiologia , Animais , Ansiedade/fisiopatologia , Complexo Nuclear Basolateral da Amígdala/citologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Condicionamento Clássico/fisiologia , Retroalimentação Fisiológica , Masculino , Núcleo Mediodorsal do Tálamo/citologia , Núcleo Mediodorsal do Tálamo/fisiologia , Camundongos , Inibição Neural , Optogenética , Estimulação Luminosa , Transtornos de Estresse Pós-Traumáticos , Fatores de TempoRESUMO
A clear understanding of the neural circuit underlying emotion regulation (ER) is important for both basic and translational research. However, a lack of evidence based on combined neuroimaging and neuromodulation techniques calls into question (1) whether the change of prefrontal-subcortical activity intrinsically and causally contributes to the ER effect; and (2) whether the prefrontal control system directly modulates the subcortical affective system. Accordingly, we combined fMRI recordings with transcranial magnetic stimulation (TMS) to map the causal connections between the PFC and subcortical affective structures (amygdala and insula). A total of 117 human adult participants (57 males and 60 females) were included in the study. The results revealed that TMS-induced ventrolateral PFC (VLPFC) facilitation led to enhanced activity in the VLPFC and ventromedial PFC (VMPFC) as well as attenuated activity in the amygdala and insula during reappraisal but not during nonreappraisal (i.e., baseline). Moreover, the activated VLPFC intensified the prefrontal-subcortical couplings via the VMPFC during reappraisal only. This study provides combined TMS-fMRI evidence that downregulating negative emotion involves the prefrontal control system suppressing the subcortical affective system, with the VMPFC serving as a crucial hub within the VLPFC-subcortical network, suggesting an indirect pathway model of the ER circuit. Our findings outline potential protocols for improving ER ability by intensifying the VLPFC-VMPFC coupling in patients with mood and anxiety disorders.SIGNIFICANCE STATEMENT Using fMRI to examine the TMS effect, we uncovered that the opposite neural changes in prefrontal (enhanced) and subcortical (attenuated) regions are not a byproduct of emotion regulation (ER); instead, this prefrontal-subcortical activity per se causally contributes to the ER effect. Furthermore, using TMS to amplify the neural changes within the ER circuit, the "bridge" role of the VMPFC is highlighted under the reappraisal versus nonreappraisal contrast. This "perturb-and-measure" approach overcomes the correlational nature of fMRI data, helping us to identify brain regions that causally support reappraisal (the VLPFC and VMPFC) and those that are modulated by reappraisal (the amygdala and insula). The uncovered ER circuit is important for understanding the neural systems underlying reappraisal and valuable for translational research.
Assuntos
Cognição , Regulação Emocional , Imageamento por Ressonância Magnética , Vias Neurais , Córtex Pré-Frontal , Estimulação Magnética Transcraniana , Feminino , Humanos , Masculino , Mapeamento Encefálico , Cognição/fisiologia , Regulação Emocional/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiologia , Ansiedade/fisiopatologia , Transtornos do Humor/fisiopatologia , Inclusão Social , Isolamento Social , Estimulação Luminosa , Tonsila do Cerebelo/fisiologia , Córtex Insular/fisiologia , Asiático , Adulto JovemRESUMO
Social play behaviour is a rewarding activity that can entail risks, thus allowing young individuals to test the limits of their capacities and to train their cognitive and emotional adaptability to challenges. Here, we tested in rats how opportunities for risk-taking during play affect the development of cognitive and emotional capacities and medial prefrontal cortex (mPFC) function, a brain structure important for risk-based decision making. Male and female rats were housed socially or social play-deprived (SPD) between postnatal day (P)21 and P42. During this period, half of both groups were daily exposed to a high-risk play environment. Around P85, all rats were tested for cognitive performance and emotional behaviour after which inhibitory currents were recorded in layer 5 pyramidal neurons in mPFC slices. We show that playing in a high-risk environment altered cognitive flexibility in both sexes and improved behavioural inhibition in males. High-risk play altered anxiety-like behaviour in the elevated plus maze in males and in the open field in females, respectively. SPD affected cognitive flexibility in both sexes and decreased anxiety-like behaviour in the elevated plus maze in females. We found that synaptic inhibitory currents in the mPFC were increased in male, but not female, rats after high-risk play, while SPD lowered prefrontal cortex (PFC) synaptic inhibition in both sexes. Together, our data show that exposure to risks during play affects the development of cognition, emotional behaviour and inhibition in the mPFC. Furthermore, our study suggests that the opportunity to take risks during play cannot substitute for social play behaviour.
Assuntos
Cognição , Córtex Pré-Frontal , Assunção de Riscos , Animais , Córtex Pré-Frontal/fisiologia , Masculino , Feminino , Ratos , Cognição/fisiologia , Jogos e Brinquedos , Comportamento Social , Ansiedade/fisiopatologia , Células Piramidais/fisiologia , Emoções/fisiologia , Comportamento Animal/fisiologiaRESUMO
Astrocytes in the central nervous system play a vital role in modulating synaptic transmission and neuronal activation by releasing gliotransmitters. The 5-HTergic neurons in the ventrolateral periaqueductal gray (vlPAG) are important in anxiety processing. However, it remains uncertain whether the regulation of astrocytic activity on vlPAG 5-HTergic neurons is involved in anxiety processing. Here, through chemogenetic manipulation, we explored the impact of astrocytic activity in the PAG on the regulation of anxiety. To determine the role of astrocytes in the control of anxiety, we induced anxiety-like behaviors in mice through foot shock and investigated their effects on synaptic transmission and neuronal excitability in vlPAG 5-HTergic neurons. Foot shock caused anxiety-like behaviors, which were accompanied with the increase of the amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs), the area of slow inward currents (SICs), and the spike frequency of action potentials (AP) in vlPAG 5-HTergic neurons. The chemogenetic inhibition of vlPAG astrocytes was found to attenuate stress-induced anxiety-like behaviors and decrease the heightened synaptic transmission and neuronal excitability of vlPAG 5-HTergic neurons. Conversely, chemogenetic activation of vlPAG astrocytes triggered anxiety-like behaviors, enhanced synaptic transmission, and increased the excitability of vlPAG 5-HTergic neurons in unstressed mice. In summary, this study has provided initial insights into the pathway by which astrocytes influence behavior through the rapid regulation of associated neurons. This offers a new perspective for the investigation of the biological mechanisms underlying anxiety.