Kwon, M. H. | bioRxiv Science

bioRxiv2026

Adolescent stress recruits a latent amygdala-dopamine circuit to drive punishment-resistant reward-seeking

Adolescent stress is a lifelong risk factor for addiction, but the underlying neural circuit changes remain unknown. Here, we show that chronic unpredictable stress in adolescent mice causes a prominent increase in punishment-resistant reward-seeking - behavior tightly linked to the diagnostic criteria for addiction - establishing a model for mechanistic investigation. Using this model, we find a "gain-of-function" in reward processing wherein persistent hyperexcitability in a subset of central amygdala (CeA) neurons projecting to the substantia nigra pars lateralis (SNL) disinhibits dopamine release in the tail of the striatum (TS), newly recruiting TS to participate in punishment-resistant reward-seeking. Normalizing circuit-specific CeA hyperexcitability or optogenetically counteracting excessive TS dopamine release prevented the increase in punishment resistance. These results identify a novel circuit mediator for the lifelong effects of adolescent stress on a core feature of addictive disorders, opening a new avenue for interventions targeted to at-risk populations with specific formative experiences.

neuroscience↗

bioRxiv2023

Recurrent activity within microcircuits of macaque dorsolateral prefrontal cortex tracks cognitive flexibility

Human and non-human primate data clearly implicate the dorsolateral prefrontal cortex (dlPFC) as critical for advanced cognitive functions1,2. It is thought that intracortical synaptic architectures within dlPFC are the integral neurobiological substrate that gives rise to these processes, including working memory, inferential reasoning, and decision-making3-7. In the prevailing model, each cortical column makes up one fundamental processing unit composed of dense intrinsic connectivity, conceptualized as the canonical cortical microcircuit3,8. Each cortical microcircuit receives sensory and cognitive information from a variety of sources which are represented by sustained activity within the microcircuit, referred to as persistent or recurrent activity4,9. Via recurrent connections within the microcircuit, activity can propagate for a variable length of time, thereby allowing temporary storage and computations to occur locally before ultimately passing a transformed representation to a downstream output4,5,10. Competing theories regarding how microcircuit activity is coordinated have proven difficult to reconcile in vivo where intercortical and intracortical computations cannot be fully dissociated5,9,11,12. Here, we interrogated the intrinsic features of isolated microcircuit networks using high-density calcium imaging of macaque dlPFC ex vivo. We found that spontaneous activity is intrinsically maintained by microcircuit architecture, persisting at a high rate in the absence of extrinsic connections. Further, using perisulcal stimulation to evoke persistent activity in deep layers, we found that activity propagates through stochastically assembled intracortical networks, creating predictable population-level events from largely non-overlapping ensembles. Microcircuit excitability covaried with individual cognitive performance, thus anchoring heuristic models of abstract cortical functions within quantifiable constraints imposed by the underlying synaptic architecture.

neuroscience↗