Biology subjects

Cash-Padgett, T.

Publications and source records attributed to Cash-Padgett, T..

4 recordsLinked to original sources

bioRxiv2023

Gaze-centered gating and re-activation of value encoding in orbitofrontal cortex

During economic choice, we often consider options in alternation, until we commit to one. Nonetheless, neuroeconomics typically ignores the dynamic aspects of deliberation. We trained macaques to perform a value-based decision-making task where two risky offers were presented in sequence at different locations of the visual field, each followed by a delay epoch where offers were invisible. Subjects looked at the offers in sequence, as expected. Surprisingly, during the delay epochs, we found that subjects still tend to look at empty locations where the visual offers were formerly presented; and, moreover, longer fixation to given empty location increases the probability of choosing the associated offer, even after controlling for the offer values. We show that activity in orbitofrontal cortex (OFC) reflects the value of the gazed offer, but also the value of the offer associated to the gazed spatial location, even if it is not the most recently viewed. This reactivation reflects a reevaluation process, as fluctuations in neural spiking during offer stimuli presentation and delays correlate with upcoming choice. Our results suggest that look-at-nothing gazing triggers the reactivation of a previously seen offer for further reevaluation, revealing novel aspects of deliberation.

neuroscience↗

bioRxiv2021

Anterior insula-associated social novelty recognition: orchestrated regulation by a local retinoic acid cascade and oxytocin signaling

BackgroundDeficits in social cognition consistently underlie functional disabilities in a wide range of psychiatric disorders. Neuroimaging studies have suggested that the anterior insula is a common core brain region that is impaired across neurological and psychiatric disorders, which include social cognition deficits. Nevertheless, neurobiological mechanisms of the anterior insula for social cognition remain elusive. MethodsTo determine the role of anterior insula in social cognition, we manipulated expression of Cyp26B1, an anterior insula-enriched molecule that is crucial for retinoic acid degradation and involved in the pathology of neuropsychiatric conditions. Social cognition was mainly assayed using the three-chamber social interaction test. We conducted multimodal analyses at the molecular, cellular, circuitry, and behavioral levels. ResultsAt the molecular/cellular level, anterior insula-mediated social novelty recognition is maintained by proper activity of the layer 5 pyramidal neurons, for which retinoic acid-mediated gene transcription can play a role. We also demonstrate that oxytocin influences the anterior insula-mediated social novelty recognition, not by direct projection of oxytocin neurons, nor by direct diffusion of oxytocin to the anterior insula, which contrasts the modes of oxytocin regulation onto the posterior insula. Instead, oxytocin affects oxytocin receptor-expressing neurons in the dorsal raphe nucleus where serotonergic neurons are projected to the anterior insula. Furthermore, we show that serotonin 5HT2C receptor expressed in the anterior insula influences social novelty recognition. ConclusionsAnterior insula plays a pivotal role in social novelty recognition that is partly regulated by a local retinoic acid cascade, but also remotely regulated by oxytocin via a non-classic mechanism.

animal behavior and cognition↗

bioRxiv2019

Astrocyte redox dysregulation causes prefrontal hypoactivity: sulforaphane treats non-ictal pathophysiology in ALDH7A1-mediated epilepsy

A fundamental but unanswered question in neuropsychiatry is whether the psychiatric symptoms of epilepsy are caused by the same or a separate pathophysiology as seizures. To address this question, we investigated a monogenic form of epilepsy (pyridoxine-dependent epilepsy) caused by aldehyde dehydrogenase 7a1 (ALDH7A1) mutations. ALDH7A1 global knockout mice exhibited both seizure-associated and affective behavioral phenotypes. However, seizure phenotypes were caused by ALDH7A1 deletion in hepatocytes whereas affective behaviors were caused by ALDH7A1 deletion in astrocytes. Deletion in astrocytes disrupted astrocyte redox homeostasis, impairing regulation of extracellular ion concentrations and reducing neuronal activity in the prelimbic cortex. Sulforaphane, which activates the NRF2 antioxidant pathway, restored prelimbic neuronal activity and rescued affective behaviors in ALDH7A1 knockout mice, but did not prevent seizures. These studies implicate astrocyte redox homeostasis and prelimbic hypoactivity in the psychiatric manifestations of a congenital form of epilepsy, which are mechanistically and therapeutically separate from the seizure pathophysiology. TeaserAntioxidant imbalance in astrocytes reduces neuronal activity, causing psychiatric symptoms in epilepsy distinct from seizures.

neuroscience↗

bioRxiv2018

Opposing pupil responses to offered and anticipated reward values

Previous studies have shown that the pupils dilate more in anticipation of larger rewards. This finding raises the possibility of a more general association between reward amount and pupil size. We tested this idea by characterizing macaque pupil responses to offered rewards during evaluation and comparison in a binary choice task. To control attention, we made use of a design in which offers occurred in sequence. By looking at pupil responses after choice but before reward, we confirmed the previously observed positive association between pupil size and anticipated reward values. Surprisingly, however, we find that pupil size is negatively correlated with the value of offered gambles before choice, during both evaluation and comparison stages of the task. These results demonstrate a functional distinction between offered and anticipated rewards, and present evidence against a narrow version of the simulation hypothesis, the idea that we represent offers by reactivating states associated with anticipating them. They also suggest that pupil size is correlated with relative, not absolute, values of offers, suggestive of an accept-reject model of comparison.

neuroscience↗