Biology subjects

Swanson, E. S.

Publications and source records attributed to Swanson, E. S..

3 recordsLinked to original sources

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↗

bioRxiv2025

Brain insulin signaling restores deficits in striatal dopamine release in overweight male mice with preexisting low D2-receptor expression

Obesity is characterized by insulin resistance, motivational impairments, and, in some cases, reduced availability of dopamine D2 receptors in the brain. However, whether the low D2 receptor levels represent a predisposing factor or a consequence of obesity, and how these processes are mechanistically linked, remains unclear. Here, we directly tested this causal relationship by selectively reducing D2 receptor density in striatal neurons. Male, but not female, mice with a low density of striatal D2 receptors consumed more food, gained more weight, and developed metabolic features of peripheral insulin resistance despite being maintained on standard chow. Motivational deficits preceded weight gain, manifesting as delayed circadian locomotor onset, reduced physical activity, and diminished effort to obtain food. In the brain, male mice with low D2 receptor density showed reduced dopamine release capacity and age-dependent alterations in brain insulin sensitivity. Prior to weight gain, brain insulin responses were blunted compared to those of controls, in which insulin potentiates dopamine release and enhances striatal acetylcholine signaling. Once overweight, however, these mice exhibited brain insulin hypersensitivity, with insulin strongly restoring dopamine release capacity. Together, these findings demonstrate that low striatal D2 receptor density predisposes male mice to an obesity-like phenotype through early dopaminergic dysfunction that precedes weight gain and is later compensated by insulin hypersensitivity in the brain.

neuroscience↗

bioRxiv2025

Cholinergic-dependent dopamine signals in mouse dorsal striatum are regulated by frontal but not sensory cortices

Everyday decisions depend on linking sensory stimuli with actions and outcomes. The striatum supports these sensorimotor associations through dopamine-dependent plasticity. Thus, the timing and magnitude of dopamine release is critical for learning. Recent work has characterized a local striatal microcircuit in which cholinergic interneurons (CINs) modulate dopamine release via acetylcholine activation of nicotinic receptors on dopamine axons. Here, we show that visual stimuli evoke dopamine responses in the dorsomedial striatum through this cholinergic-dependent mechanism. Using anatomical and functional methods to identify which pathways elicit these signals, we found that visual and auditory cortices that project to the dorsomedial striatum lack robust connectivity to CINs and were unable to drive cholinergic-dependent dopamine release. In contrast, frontal cortical regions, including the prelimbic and anterior cingulate cortices, strongly recruited CINs and acetylcholine, producing robust dopamine release both ex vivo and in vivo. These frontal corticostriatal projections are activated by visual stimuli, representing a possible pathway by which visual information reaches the dorsomedial striatum to evoke dopamine. These findings reveal a fundamental distinction between sensory and frontal cortical inputs to the striatum, demonstrating that only the latter evoke cholinergic-dependent dopamine signaling. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.

neuroscience↗