Oscar Gonzalez
Instructor, Psychiatry and Behavioral Sciences
Academic Appointments
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Instructor, Psychiatry and Behavioral Sciences
All Publications
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Phosphorylation of pyruvate dehydrogenase inversely associates with neuronal activity.
Neuron
2024
Abstract
For decades, the expression of immediate early genes (IEGs) such as FOS has been the most widely used molecular marker representing neuronal activation. However, to date, there is no equivalent surrogate available for the decrease of neuronal activity. Here, we developed an optogenetic-based biochemical screen in which population neural activities can be controlled by light with single action potential precision, followed by unbiased phosphoproteomic profiling. We identified that the phosphorylation of pyruvate dehydrogenase (pPDH) inversely correlated with the intensity of action potential firing in primary neurons. In in vivo mouse models, monoclonal antibody-based pPDH immunostaining detected activity decreases across the brain, which were induced by a wide range of factors including general anesthesia, chemogenetic inhibition, sensory experiences, and natural behaviors. Thus, as an inverse activity marker (IAM) in vivo, pPDH can be used together with IEGs or other cell-type markers to profile and identify bi-directional neural dynamics induced by experiences or behaviors.
View details for DOI 10.1016/j.neuron.2023.12.015
View details for PubMedID 38266644
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A cluster of neuropeptide S neurons regulates breathing and arousal.
Current biology : CB
2023
Abstract
Neuropeptide S (NPS) is a highly conserved peptide found in all tetrapods that functions in the brain to promote heightened arousal; however, the subpopulations mediating these phenomena remain unknown. We generated mice expressing Cre recombinase from the Nps gene locus (NpsCre) and examined populations of NPS+ neurons in the lateral parabrachial area (LPBA), the peri-locus coeruleus (peri-LC) region of the pons, and the dorsomedial thalamus (DMT). We performed brain-wide mapping of input and output regions of NPS+ clusters and characterized expression patterns of the NPS receptor 1 (NPSR1). While the activity of all three NPS+ subpopulations tracked with vigilance state, only NPS+ neurons of the LPBA exhibited both increased activity prior to wakefulness and decreased activity during REM sleep, similar to the behavioral phenotype observed upon NPSR1 activation. Accordingly, we found that activation of the LPBA but not the peri-LC NPS+ neurons increased wake and reduced REM sleep. Furthermore, given the extended role of the LPBA in respiration and the link between behavioral arousal and breathing rate, we demonstrated that the LPBA but not the peri-LC NPS+ neuronal activation increased respiratory rate. Together, our data suggest that NPS+ neurons of the LPBA represent an unexplored subpopulation regulating breathing, and they are sufficient to recapitulate the sleep/wake phenotypes observed with broad NPS system activation.
View details for DOI 10.1016/j.cub.2023.11.018
View details for PubMedID 38056461
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Adolescent sleep defects and dopaminergic hyperactivity in mice with a schizophrenia-linked Shank3 mutation.
Sleep
2023
Abstract
Shank3 is a shared risk gene for autism spectrum disorders and schizophrenia. Sleep defects have been characterized for autism models with Shank3 mutations, however, evidence has been lacking for the potential sleep defects caused by Shank3 mutation associated with schizophrenia and how early in development these defects may occur. Here we characterized the sleep architecture of adolescent mice carrying a schizophrenia-linked, R1117X mutation in Shank3. We further employed GRABDA dopamine sensor and fiber photometry to record dopamine release in the nucleus accumbens during sleep/wake states. Our results show that homozygous mutant R1117X mice have significantly reduced sleep in the dark phase during adolescence, altered electroencephalogram power especially during the rapid-eye-movement sleep, and dopamine hyperactivity during sleep but not during wakefulness. Further analyses suggest that these adolescent defects in sleep architecture and dopaminergic neuromodulation tightly correlate with the social novelty preference later in adulthood and predict adult social performance during same-sex social interactions. Our results provide novel insights to the sleep phenotypes in mouse models of schizophrenia and the potential use of developmental sleep as a predictive metric for adult social symptoms. Together with recent studies in other Shank3 models, our work underscores the idea that Shank3-involved circuit disruptions may be one of the shared pathologies in certain types of schizophrenia and autism. Future research is needed to establish the causal relationship among adolescent sleep defects, dopaminergic dysregulation, and adult behavioral changes in Shank3 mutation animals and other models.
View details for DOI 10.1093/sleep/zsad131
View details for PubMedID 37144901
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Optogenetic and pharmacological interventions link hypocretin neurons to impulsivity in mice.
Communications biology
2023; 6 (1): 74
Abstract
Neurons in the lateral hypothalamus expressing the neuropeptide Hypocretin, also known as orexin, are known critical modulators of arousal stability. However, their role in the different components of the arousal construct such as attention and decision making is poorly understood. Here we study Hypocretin neuronal circuit dynamics during stop action impulsivity in a Go/NoGo task in mice. We show that Hypocretin neuronal activity correlates with anticipation of reward. We then assessed the causal role of Hypocretin neuronal activity using optogenetics in a Go/NoGo task. We show that stimulation of Hypocretin neurons during the cue period dramatically increases the number of premature responses. These effects are mimicked by amphetamine, reduced by atomoxetine, a norepinephrine uptake inhibitor, and blocked by a Hypocretin receptor 1 selective antagonist. We conclude that Hypocretin neurons have a key role in the integration of salient stimuli during wakefulness to produce appropriate and timely responses to rewarding and aversive cues.
View details for DOI 10.1038/s42003-023-04409-w
View details for PubMedID 36658362