Striatum processes a wide range of functions including goal-directed behavior and habit formation, respectively encoded by the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). GABAergic feedforward inhibition is known to control the integration of cortical information by striatal projection neurons (SPNs). Here we questioned whether this control is specific between distinct striatal functional territories. Using opto-activation and opto-inhibition of identified GABAergic interneurons, we found that different circuits are engaged in DLS and DMS, both ex vivo and in vivo: while parvalbumin interneurons efficiently control SPNs in DLS, somatostatin interneurons control SPNs in DMS. Moreover, both parvalbumin and somatostatin interneurons use a dual hyperpolarizing/depolarizing effect to control cortical input integration depending on SPN activity state: GABAergic interneurons potently inhibit spiking SPNs while in resting SPNs, they favor cortical activity summation via a depolarizing effect. Our findings establish that striatal GABAergic interneurons exert efficient territory-specific and state-dependent control of SPN activity and functional output.

Activity of the mesolimbic dopamine system has long been implicated in encoding primary rewards and contributing to the addictive properties of drugs of abuse. Dopamine neurons in the ventral tegmental area (VTA) of the midbrain typically show patterns of spontaneous burst activity that align with the onset of salient events or rewarding stimuli, resulting in phasic dopamine release in the nucleus accumbens (NAc). Fiber photometry is increasingly being used as an accessible technique to quantify neural activity with high temporal resolution at sensors offering signal specificity in stable recordings over extended periods of time. It has been well established by multiple techniques that opioids increase mesolimbic dopamine activity, likely through disinhibition of VTA neurons. Here we used fiber photometry to compare sub-second transient events from VTA neurons with GCaMP6f and dopamine release in the lateral shell of the NAc with dLight1.3b and GRABDA2h in response to morphine treatment. In weekly sessions, one dose of morphine was administered in escalating order (2.5, 5,7.5, and 10 mg/kg, intraperitoneal). Consistent with prior literature, both GCaMP6f in VTA neurons and dLight1.3b in NAc showed patterns of increased signal following morphine treatment. In contrast, morphine suppressed transient activity at GRABDA2h sensors. Further analyses of whole signal streams from each sensor showed a generalized increase, but reduction in variability of the GRABDA2h signal, consistent with the interpretation of sensor saturation. Such results emphasize the importance of the inclusion of appropriate controls to contextualize the interpretation of biosensor responses, particularly in response to pharmacological treatment.

Acetylcholine (ACh) signaling in the basolateral amygdala (BLA) has been implicated in salience-related processing and associative learning, yet the circuit mechanisms that regulate its dynamics remain poorly understood. Here we show that BLA ACh dynamically represented salience. In the mouse nucleus accumbens (NAc), D1-expressing medium spiny neurons (MSNs) selectively promote, whereas D2-expressing MSNs selectively suppress, ACh release in the BLA but not in the cortex or hippocampus. NAc D1 and D2 MSNs regulate BLA ACh by disinhibiting and inhibiting cholinergic neurons in the substantia innominata (SI), respectively. Axon terminals of D1 and D2 MSNs in the SI exhibit differential responses to salient stimuli and modulate BLA ACh dynamics. Closed-loop optogenetic manipulations of NAc D1 and D2 projections to the SI have opposing effects on associative learning. Our findings uncover an unconventional role of striatal MSNs in modulating behavioral significance through the regulation of salience-related amygdalar ACh activity.

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 primary visual cortex and early sensory areas that project to the striatum exhibited only weak connectivity to CINs, despite robust connectivity to projection neurons, and were unable to drive dopamine release. In contrast, frontal cortical regions, including the prelimbic and anterior cingulate cortices, strongly recruited CINs and acetylcholine, producing robust dopamine release both and . These findings reveal a fundamental distinction between sensory and frontal cortical inputs to the striatum, demonstrating that only the latter provide effective access to cholinergic-dependent dopamine signaling. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.