Biology subjects

Kwan, A. C.

Publications and source records attributed to Kwan, A. C..

25 records · Page 2Linked to original sources

bioRxiv2021

Pupil correlates of decision variables in mice playing a competitive mixed-strategy game

In a competitive game involving an animal and an opponent, the outcome is contingent on the choices of both players. To succeed, the animal must continually adapt to competitive pressure, or else risk being exploited and lose out on rewards. In this study, we demonstrate that head-fixed mice can be trained to play the iterative competitive game matching pennies against a virtual computer opponent. We find that the animals performance is well described by a hybrid computational model that includes Q-learning and choice kernels. Comparing between matching pennies and a non-competitive two-armed bandit task, we show that the tasks encourage animals to operate at different regimes of reinforcement learning. To understand the involvement of neuromodulatory mechanisms, we measure fluctuations in pupil size and use multiple linear regression to relate the trial-by-trial transient pupil responses to decision-related variables. The analysis reveals that pupil responses are modulated by observable variables, including choice and outcome, as well as latent variables for value updating, but not action selection. Collectively, these results establish a paradigm for studying competitive decision-making in head-fixed mice and provide insights into the role of arousal-linked neuromodulation in the decision process.

neuroscience↗

bioRxiv2021

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo

Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and time scale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to [~]10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 hours and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.

neuroscience↗

bioRxiv2020

Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

neuroscience↗

bioRxiv2019

Cumulative effects of social stress on reward-guided actions and prefrontal cortical activity

When exposed to chronic social stress, animals display behavioral changes that are relevant to depressive-like phenotypes. However, the cascading relationship between incremental stress exposure and neural dysfunctions over time remains incompletely understood. Here we characterize the longitudinal effect of social defeat on goal-directed actions and prefrontal cortical activity in mice, using a head-fixed sucrose preference task and two-photon calcium imaging. Behaviorally, stress-induced loss of reward sensitivity intensifies over days. Motivational anhedonia, the failure to translate positive reinforcements into future actions, requires multiple sessions of stress exposure to become fully established. For neural activity, individual layer 2/3 pyramidal neurons in the Cg1 and M2 subregions of the medial prefrontal cortex have heterogeneous responses to stress. Changes in ensemble activity differ significantly between susceptible and resilient animals after the first defeat session, and continue to diverge following successive stress episodes before reaching persistent abnormal levels. Collectively, these results demonstrate that the cumulative impact of an ethologically relevant stress can be observed at the level of cellular activity of individual prefrontal neurons. The distinct neural responses associated with resilience versus susceptibility raises the hypothesis that the negative impact of social stress is neutralized in resilient animals, in part through an adaptive reorganization of prefrontal cortical activity.

neuroscience↗

bioRxiv2019

A computational model for learning from repeated trauma

AbstracTraumatic events can lead to lifelong inflexible adaptations in threat perception and behavior which characterize posttraumatic stress disorder (PTSD). This process involves associations between sensory cues and internal states of threat and then generalization of the threat responses to previously neutral cues. However, most formulations neglect adaptations to threat that are not specific to those associations. In order to incorporate non-associative responses to threat, we propose a computational theory of PTSD based on adaptation to the frequency of traumatic events using a reinforcement learning momentum model. Recent threat prediction errors generate momentum that influences subsequent threat perception in novel contexts. This model fits data acquired from a mouse model of PTSD, in which unpredictable footshocks in one context accelerate threat learning in a novel context. The theory is also consistent with epidemiological data showing that PTSD incidence increases with the number of traumatic events, as well as the disproportionate impact of early life trauma. Since the theory proposes that PTSD relates to the average of recent threat prediction errors rather than the strength of a specific association, it makes novel predictions for the treatment of PTSD.

animal behavior and cognition↗

bioRxiv2019

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and then more sustained antidepressant effects. A key targeted brain region is the prefrontal cortex, and the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine may act preferentially on GABAergic neurons. However, cortical GABAergic neurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that administration of ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamines actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.

neuroscience↗

bioRxiv2018

Enhanced population coding for rewarded choices in the medial frontal cortex of the mouse

Instrumental behavior is characterized by the selection of actions based on the degree to which they lead to a desired outcome. However, we lack a detailed understanding of how rewarded actions are reinforced and preferentially implemented. In rodents, the medial frontal cortex is hypothesized to play an important role in this process, based in part on its capacity to encode chosen actions and their outcomes. We therefore asked how neural representations of choice and outcome might interact to facilitate instrumental behavior. To investigate this question, we imaged neural ensemble activity in layer 2/3 of the secondary motor region (M2) while mice engaged in a two-choice auditory discrimination task with probabilistic outcomes. Correct choices could result in one of three reward amounts (single-, double-, or omitted-reward), which allowed us to measure neural and behavioral effects of reward magnitude, as well as its categorical presence or absence. Single-unit and population decoding analyses revealed a consistent influence of outcome on choice signals in M2. Specifically, rewarded choices were more robustly encoded relative to unrewarded choices, with little dependence on the exact magnitude of reinforcement. Our results provide insight into the integration of past choices and outcomes in the rodent brain during instrumental behavior.

neuroscience↗