RESUMEN
Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Cuerpo Estriado , Proteínas del Tejido Nervioso , Corteza Prefrontal , Inhibición Prepulso , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Humanos , Ratones , Proteínas del Tejido Nervioso/metabolismo , Corteza Prefrontal/metabolismo , Inhibición Prepulso/fisiología , Reflejo de Sobresalto/fisiología , Filtrado Sensorial/fisiologíaRESUMEN
Therapeutic development for mental disorders has been slow despite the high worldwide prevalence of illness. Unfortunately, cellular and circuit insights into disease etiology have largely failed to generalize across individuals that carry the same diagnosis, reflecting an unmet need to identify convergent mechanisms that would facilitate optimal treatment. Here, we discuss how mesoscale networks can encode affect and other cognitive processes. These networks can be discovered through electrical functional connectome (electome) analysis, a method built upon explainable machine learning models for analyzing and interpreting mesoscale brain-wide signals in a behavioral context. We also outline best practices for identifying these generalizable, interpretable, and biologically relevant networks. Looking forward, translational electome analysis can span species and various moods, cognitive processes, or other brain states, supporting translational medicine. Thus, we argue that electome analysis provides potential translational biomarkers for developing next-generation therapeutics that exhibit high efficacy across heterogeneous disorders.
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Conectoma , Trastornos Mentales , Humanos , Imagen por Resonancia Magnética/métodos , Encéfalo , Conectoma/métodos , Aprendizaje AutomáticoRESUMEN
In rodents, anxiety is charactered by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system are fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain-state. The network is composed of circuits widely implicated in anxiety behavior, it generalizes across many behavioral contexts that induce anxiety, and it fails to encode multiple behavioral contexts that do not. Strikingly, the activity of this network is also principally altered in two mouse models of depression. Thus, we establish a network-level process whereby the brain encodes anxiety in health and disease.
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Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced levels of antiviral proteins (AVPs) and circadian regulators, including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin, and such circadian control of AVPs was diminished by disruption of immune cell IL-27 signaling and deletion of Bmal1/Clock genes in mouse skin, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment with the circadian-enhancing agents nobiletin and SR8278 reduced infection of herpes simplex virus 1 in epidermal explants and human keratinocytes in a BMAL1/CLOCK-dependent manner. Circadian-enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.
Asunto(s)
Factores de Transcripción ARNTL , Ritmo Circadiano , Humanos , Animales , Ratones , Anciano , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Ritmo Circadiano/fisiología , Piel/metabolismo , Envejecimiento , Queratinocitos/metabolismoRESUMEN
Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced antiviral proteins (AVPs) and circadian regulators including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin and such circadian-control of AVPs was diminished by disruption of immune cell interleukin 27 signaling and deletion of Bmal1/Clock genes in mouse skins, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment of circadian enhancing agents, nobiletin and SR8278, reduced infection of herpes simplex virus 1 (HSV1) in epidermal explants and human keratinocytes in a Bmal1/Clock-dependent manner. Circadian enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.
RESUMEN
OBJECTIVE: To determine whether the ß1 integrin/caveolin-1 signaling complex plays a role in shear stress regulation of RhoA activity . METHODS AND RESULTS: Hemodynamic shear stress influences the phenotype of the endothelium. Integrins and RhoA are essential components in the process that allows endothelial cells to adapt to flow. However, the signaling mechanisms that relay from integrins to RhoA are not well defined. Bovine aortic endothelial cells were subjected to laminar shear stress (10 dyne/cm(2)) for up to 6 hours. ß1 integrin blockade inhibited Src family kinases and p190RhoGAP tyrosine phosphorylation observed after the immediate onset of shear stress. Depletion of caveolin-1 blocked the decline in p190RhoGAP tyrosine phosphorylation observed at later points by sustaining Src family kinase activity. The manipulation of ß1 integrin and caveolin-1 also altered shear regulation of RhoA activity. More importantly, cells depleted of p190RhoGAP showed faulty temporal regulation of RhoA activity. Each of these treatments attenuated actin reorganization induced by flow. Similarly, stress fibers failed to form in endothelial cells exposed to enhanced blood flow in caveolin-1 knockout mice. CONCLUSIONS: Our studies demonstrate that p190RhoGAP links integrins and caveolin-1/caveolae to RhoA in a mechanotransduction cascade that participates in endothelial adaptation to flow.
Asunto(s)
Actinas/metabolismo , Arterias Carótidas/metabolismo , Caveolina 1/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Integrina beta1/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal/fisiología , Proteína de Unión al GTP rhoA/metabolismo , Adaptación Fisiológica/fisiología , Animales , Fenómenos Biomecánicos , Bovinos , Caveolina 1/genética , Células Cultivadas , Endotelio Vascular/metabolismo , Ratones , Ratones Noqueados , Modelos Animales , Estrés MecánicoRESUMEN
The architecture whereby activity across many brain regions integrates to encode individual appetitive social behavior remains unknown. Here we measure electrical activity from eight brain regions as mice engage in a social preference assay. We then use machine learning to discover a network that encodes the extent to which individual mice engage another mouse. This network is organized by theta oscillations leading from prelimbic cortex and amygdala that converge on the ventral tegmental area. Network activity is synchronized with cellular firing, and frequency-specific activation of a circuit within this network increases social behavior. Finally, the network generalizes, on a mouse-by-mouse basis, to encode individual differences in social behavior in healthy animals but fails to encode individual behavior in a 'high confidence' genetic model of autism. Thus, our findings reveal the architecture whereby the brain integrates distributed activity across timescales to encode an appetitive brain state underlying individual differences in social behavior.
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Conducta Apetitiva , Encéfalo , Amígdala del Cerebelo , Animales , Encéfalo/fisiología , Ratones , Conducta Social , Área Tegmental VentralRESUMEN
COVID-19 has not only dramatically changed the way we live, it has also impacted how we die and how we grieve. With more and more Americans dying in ICU settings, away from family, and more funerals being held virtually, the pandemic has seriously curtailed normal expressions of grief and cultural mourning. Given the CDC guidelines for funerals and social distancing, simple human touch is no longer a mitigating force against prolonged grief. So, while one epidemic has a face and a name, we point to a second, more silent yet potentially equally devastating one, unacknowledged grief, and emphasize how policy can be a current therapeutic. We can wait for a vaccine, but we can also act now through thoughtful policymaking that acknowledges this second epidemic.
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COVID-19/psicología , Pesar , Pandemias , Políticas , Conducta Ceremonial , Privación del Duelo , Humanos , Distanciamiento FísicoRESUMEN
Psychological stress contributes to the onset and exacerbation of nearly all neuropsychiatric disorders. Individual differences in stress-regulatory circuits can therefore dramatically affect vulnerability to these illnesses. Here we identify neural circuit mechanisms underlying individual differences in vulnerability to stress using a murine model of chronic social defeat stress. In chronically stressed mice, we find that the degree of prefrontal cortex (PFC) control of amygdala activity predicts stress susceptibility in individual mice. Critically, we also find that individual differences in PFC activation (that is, reactivity) during exposure to an aggressor mouse predict the emergence stress-induced behavioural deficits in stress-naïve mice. Finally, we show that naturally occurring differences in PFC reactivity directly correspond to the intrinsic firing rate of PFC neurons. This demonstrates that naturally occurring differences in PFC function underlie individual differences in vulnerability to stress, raising the hypothesis that PFC modulation may prevent stress-induced psychiatric disorders.