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1.
Cell ; 186(3): 543-559.e19, 2023 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-36669484

RESUMO

Learning has been associated with modifications of synaptic and circuit properties, but the precise changes storing information in mammals have remained largely unclear. We combined genetically targeted voltage imaging with targeted optogenetic activation and silencing of pre- and post-synaptic neurons to study the mechanisms underlying hippocampal behavioral timescale plasticity. In mice navigating a virtual-reality environment, targeted optogenetic activation of individual CA1 cells at specific places induced stable representations of these places in the targeted cells. Optical elicitation, recording, and modulation of synaptic transmission in behaving mice revealed that activity in presynaptic CA2/3 cells was required for the induction of plasticity in CA1 and, furthermore, that during induction of these place fields in single CA1 cells, synaptic input from CA2/3 onto these same cells was potentiated. These results reveal synaptic implementation of hippocampal behavioral timescale plasticity and define a methodology to resolve synaptic plasticity during learning and memory in behaving mammals.


Assuntos
Região CA1 Hipocampal , Hipocampo , Camundongos , Animais , Região CA1 Hipocampal/fisiologia , Hipocampo/fisiologia , Plasticidade Neuronal/fisiologia , Aprendizagem/fisiologia , Neurônios , Transmissão Sináptica/fisiologia , Mamíferos
2.
Cell ; 185(19): 3568-3587.e27, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36113428

RESUMO

Computational analysis of cellular activity has developed largely independently of modern transcriptomic cell typology, but integrating these approaches may be essential for full insight into cellular-level mechanisms underlying brain function and dysfunction. Applying this approach to the habenula (a structure with diverse, intermingled molecular, anatomical, and computational features), we identified encoding of reward-predictive cues and reward outcomes in distinct genetically defined neural populations, including TH+ cells and Tac1+ cells. Data from genetically targeted recordings were used to train an optimized nonlinear dynamical systems model and revealed activity dynamics consistent with a line attractor. High-density, cell-type-specific electrophysiological recordings and optogenetic perturbation provided supporting evidence for this model. Reverse-engineering predicted how Tac1+ cells might integrate reward history, which was complemented by in vivo experimentation. This integrated approach describes a process by which data-driven computational models of population activity can generate and frame actionable hypotheses for cell-type-specific investigation in biological systems.


Assuntos
Habenula , Recompensa , Dinâmica Populacional
3.
Nature ; 615(7951): 292-299, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36859543

RESUMO

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 Artificial
4.
Int J Mol Sci ; 23(11)2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35682574

RESUMO

Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent pathological feature of neurodegenerative diseases is the toxic buildup of misfolded protein aggregates and inclusion bodies accompanied by an impairment in proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress and neurodegenerative pathology in cellular and animal models as well as in human patients. The contribution of mutant or misfolded protein-triggered ER stress and its associated signaling events, such as unfolded protein response (UPR), to the pathophysiology of various neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, amyotrophic lateral sclerosis, and prion disease, is described here. Impaired UPR action is commonly attributed to exacerbated ER stress, pathogenic protein aggregate accumulation, and deteriorating neurodegenerative pathologies. Thus, activating certain UPR components has been shown to alleviate ER stress and its associated neurodegeneration. However, uncontrolled activation of some UPR factors has also been demonstrated to worsen neurodegenerative phenotypes, suggesting that detailed molecular mechanisms around ER stress and its related neurodegenerations should be understood to develop effective therapeutics against aging-associated neurological syndromes. We also discuss current therapeutic endeavors, such as the development of small molecules that selectively target individual UPR components and address ER stress in general.


Assuntos
Estresse do Retículo Endoplasmático , Doenças Neurodegenerativas , Animais , Autofagia , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Humanos , Doenças Neurodegenerativas/metabolismo , Resposta a Proteínas não Dobradas
5.
Science ; 383(6686): 967-970, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38422134

RESUMO

Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory synapses on a timescale of seconds during behavior.


Assuntos
Região CA1 Hipocampal , Endocanabinoides , Potenciais Pós-Sinápticos Inibidores , Sinapses , Transmissão Sináptica , Animais , Camundongos , Endocanabinoides/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Sinalização do Cálcio , Região CA1 Hipocampal/fisiologia , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/fisiologia , Masculino , Feminino , Camundongos Knockout
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