RESUMO
Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states1-12. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use13,14, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1-3-Hz rhythm in layer 5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed-including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found that rhythmic optogenetic activation of retrosplenial cortex layer 5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.
Assuntos
Ondas Encefálicas/fisiologia , Córtex Cerebral/fisiologia , Transtornos Dissociativos/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Córtex Cerebral/citologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Transtornos Dissociativos/diagnóstico por imagem , Eletrofisiologia , Feminino , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Ketamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Optogenética , Autorrelato , Tálamo/citologia , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Tálamo/fisiologiaRESUMO
Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.
Assuntos
Espinhas Dendríticas/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico/fisiopatologia , Tálamo/fisiologia , Estriado Ventral/fisiologia , Animais , Comportamento Animal/fisiologia , Suscetibilidade a Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Recompensa , Comportamento Social , Estriado Ventral/citologiaRESUMO
The dorsal striatum, which consists of the caudate and putamen, is the gateway to the basal ganglia. It receives convergent excitatory afferents from cortex and thalamus and forms the origin of the direct and indirect pathways, which are distinct basal ganglia circuits involved in motor control. It is also a major site of activity-dependent synaptic plasticity. Striatal plasticity alters the transfer of information throughout basal ganglia circuits and may represent a key neural substrate for adaptive motor control and procedural memory. Here, we review current understanding of synaptic plasticity in the striatum and its role in the physiology and pathophysiology of basal ganglia function.
Assuntos
Gânglios da Base/fisiologia , Movimento/fisiologia , Neostriado/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Gânglios da Base/anatomia & histologia , Doenças dos Gânglios da Base/fisiopatologia , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/fisiologia , Humanos , Memória/fisiologia , Neostriado/anatomia & histologia , Vias Neurais/anatomia & histologia , Vias Neurais/fisiologia , Transmissão Sináptica/fisiologia , Tálamo/anatomia & histologia , Tálamo/fisiologiaRESUMO
Drug-induced adaptations in the prefrontal cortex (PFC) contribute to several core aspects of addictive behaviors, but the underlying neuronal processes remain essentially unknown. Here, we demonstrate that repeated in vivo exposure to cocaine persistently reduces the voltage-gated K+ current (VGKC) in PFC pyramidal neurons, resulting in enhanced membrane excitability. Analysis of dopamine D1-class receptor (D1R)-mediated modulation of VGKC indicates that, despite the absence of direct D1R stimulation, downstream D1 signaling (the cAMP/protein kinase A pathway) is increased during withdrawal from chronic cocaine treatment and plays a central role in the drug-induced membrane plasticity in PFC. This long-lasting, cocaine-induced plasticity of membrane excitability in PFC pyramidal neurons may contribute to the impaired decision making and drug craving that characterize cocaine withdrawal.