RESUMEN
Optimizing behavioral strategy requires belief updating based on new evidence, a process that engages higher cognition. In schizophrenia, aberrant belief dynamics may lead to psychosis, but the mechanisms underlying this process are unknown, in part, due to lack of appropriate animal models and behavior readouts. Here, we address this challenge by taking two synergistic approaches. First, we generate a mouse model bearing patient-derived point mutation in Grin2a (Grin2aY700X+/-), a gene that confers high-risk for schizophrenia and recently identified by large-scale exome sequencing. Second, we develop a computationally trackable foraging task, in which mice form and update belief-driven strategies in a dynamic environment. We found that Grin2aY700X+/- mice perform less optimally than their wild-type (WT) littermates, showing unstable behavioral states and a slower belief update rate. Using functional ultrasound imaging, we identified the mediodorsal (MD) thalamus as hypofunctional in Grin2aY700X+/- mice, and in vivo task recordings showed that MD neurons encoded dynamic values and behavioral states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopied Grin2aY700X+/- mice, and enhancing MD activity rescued task deficits in Grin2aY700X+/- mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction, and a potential target for future therapeutics.
RESUMEN
Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like states induced by the NMDAR antagonist phencyclidine and subsequent rescue by two atypical antipsychotic drugs (AAPDs), risperidone and clozapine, and the classical APD haloperidol. The psychotomimetic effects of phencyclidine were associated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. Phencyclidine boosted prefrontal oscillatory power at atypical bands within delta, gamma, and high frequency ranges, while irregular cross-frequency and spike-LFP coupling emerged. In the hippocampus, phencyclidine enhanced delta rhythms but suppressed theta oscillations, theta-gamma coupling, and theta-beta spike-LFP coupling. Baseline interregional theta-gamma coupling, theta phase coherence, and hippocampus-to-cortex theta signals were redirected to delta frequencies. Risperidone and clozapine, but not haloperidol, reduced phencyclidine-induced prefrontal and cortical-hippocampal hypersynchrony. None of the substances restored hippocampal and circuit desynchronization. These results suggest that AAPDs, but not typical APDs, target prefrontal-hippocampal pathways to elicit antipsychotic action. We investigated whether the affinity of AAPDs for serotonin receptors could explain their distinct effects. Serotonin 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT reduced prefrontal hypersynchronization. Our results point to fundamentally different neural mechanisms underlying the action of atypical versus typical APDs with selective contribution of serotonin receptors.
Asunto(s)
Antipsicóticos , Clozapina , Trastornos Psicóticos , Receptor de Serotonina 5-HT1A , Receptor de Serotonina 5-HT2A , Animales , Antipsicóticos/farmacología , Clozapina/farmacología , Haloperidol/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Fenciclidina/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Risperidona/farmacología , Antagonistas de la Serotonina/farmacologíaRESUMEN
General anesthesia (GA) is a reversible drug-induced state of altered arousal required for more than 60,000 surgical procedures each day in the United States alone. Sedation and unconsciousness under GA are associated with stereotyped electrophysiological oscillations that are thought to reflect profound disruptions of activity in neuronal circuits that mediate awareness and cognition. Computational models make specific predictions about the role of the cortex and thalamus in these oscillations. In this paper, we provide in vivo evidence in rats that alpha oscillations (10-15 Hz) induced by the commonly used anesthetic drug propofol are synchronized between the thalamus and the medial prefrontal cortex. We also show that at deep levels of unconsciousness where movement ceases, coherent thalamocortical delta oscillations (1-5 Hz) develop, distinct from concurrent slow oscillations (0.1-1 Hz). The structure of these oscillations in both cortex and thalamus closely parallel those observed in the human electroencephalogram during propofol-induced unconsciousness. During emergence from GA, this synchronized activity dissipates in a sequence different from that observed during loss of consciousness. A possible explanation is that recovery from anesthesia-induced unconsciousness follows a "boot-up" sequence actively driven by ascending arousal centers. The involvement of medial prefrontal cortex suggests that when these oscillations (alpha, delta, slow) are observed in humans, self-awareness and internal consciousness would be impaired if not abolished. These studies advance our understanding of anesthesia-induced unconsciousness and altered arousal and further establish principled neurophysiological markers of these states.
Asunto(s)
Anestesia General , Ondas Encefálicas , Modelos Neurológicos , Red Nerviosa/fisiopatología , Corteza Prefrontal/fisiopatología , Propofol/farmacología , Inconsciencia/fisiopatología , Animales , Ratas , Ratas Sprague-Dawley , Inconsciencia/inducido químicamenteRESUMEN
OBJECTIVE: Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a high-frequency oscillation (HFO) which power is modulated nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PDs) of ketamine and the observed HFO power. APPROACH: In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by an HFO observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. MAIN RESULTS: We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. SIGNIFICANCE: Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent range of effects that ketamine has.