Biology subjects

Guven, E. B.

Publications and source records attributed to Guven, E. B..

4 recordsLinked to original sources

bioRxiv2026

Nicotinic control of dopamine release shapes striatal output and engages adaptive action selection.

Acetylcholine and dopamine significantly modulate striatal circuits and are essential for reward learning and action selection. Cholinergic interneurons can locally trigger dopamine release through beta2-containing nicotinic acetylcholine receptors expressed on dopamine axons1-3. However, the causal contribution of this local cholinergic control of dopamine to behaviour and striatal output remains unresolved, with recent studies reaching contrasting conclusions about the extent and behavioural relevance of local acetylcholine-dopamine coupling4-6. Here, to directly test the causal contribution of this pathway, we conditionally deleted beta2-containing nicotinic acetylcholine receptors from midbrain neurons in adult mice. This manipulation selectively abolished cholinergic interneuron-evoked dopamine release in the striatum. In a reward-based instrumental task, mice lacking this pathway showed decrements in effort that depended on the reinforcement context, and failed to adjust actions in a choice task when effort and reward costs varied. Substantia nigra beta2-containing nicotinic acetylcholine receptor deletion also markedly weakened cholinergic interneuron-mediated disynaptic inhibition of striatal projection neurons, showing that disruption of beta2-dependent cholinergic control of dopamine alters how cholinergic activity is transmitted to striatal output. Together, these findings establish the importance of local acetylcholine-dopamine coupling for regulating striatal output and influencing whether actions are sustained and adjusted as effort, reward, and outcomes change.

neuroscience↗

bioRxiv2026

Long-range inhibitory control of cholinergic network dynamics in the striatum.

Striatal cholinergic interneurons (CINs) exhibit a transient pause in tonic firing in response to salient stimuli, a hallmark of reinforcement learning that becomes synchronized with learning. Although thalamostriatal and dopaminergic inputs have been implicated in this pause, the underlying circuit mechanisms remain unclear. Here, we combine optogenetics, electrophysiology, and genetic approaches to examine inhibitory interactions within the CIN network. Synchronized activation of CINs in striatal slices elicited robust feedback inhibition in CINs, suppressing firing and generating pause-like responses. This inhibition was mediated by GABAA receptors and required {beta}2-containing nicotinic acetylcholine receptors ({beta}2-nAChR), and could be recruited by thalamostriatal activation. Dopamine is not required for this circuit but modulates it via D2 receptors. Surprisingly, cell-type-specific silencing and striatal {beta}2-nAChR deletion excluded local GABAergic sources, whereas retrograde {beta}2-nAChR deletion abolished inhibition, revealing an extrastriatal pathway. These findings identify a long-range inhibitory mechanism linking synchronized cholinergic activity to pause generation in striatal circuits.

neuroscience↗

bioRxiv2026

Cholinergic interneuron control of GABAergic circuits targeting spiny projection neurons is disrupted in parkinsonian models

Parkinsons disease (PD) is known to alter the intrinsic properties of striatal cholinergic interneurons (ChIs). However, how PD shapes ChI control of intrastriatal GABAergic circuits regulating principal spiny projection neurons (SPNs) is unknown. To fill this gap, striatal circuits in healthy and parkinsonian mice were interrogated. In ex vivo brain slices from healthy mice, optogenetic stimulation of ChIs evoked GABAA receptor currents in both indirect and direct pathway SPNs that were attributable to nicotinic acetylcholine receptor (nAChR)-mediated activation of GABAergic interneurons (GIs). Simulations suggested that this circuit exerts a state-dependent control of SPN dendritic integration that was modulated by concomitant muscarinic receptor signaling. Surprisingly, in mouse models of prodromal and parkinsonian states, the ability of ChIs to engage this intrastriatal circuitry was disrupted because interneurons down-regulated nicotinic AChRs. Taken together, these studies suggest that impaired ChI control of GABAergic interneurons contributes to behavioral deficits in both prodromal and clinical PD states.

neuroscience↗

bioRxiv2021

Cholinergic control of striatal GABAergic microcircuits

AO_SCPLOWBSTRACTC_SCPLOWCholinergic interneurons (CINs) are essential elements of striatal circuits and behaviors. While acetylcholine signaling via muscarinic receptors (mAChRs) have been well studied, more recent data indicate that postsynaptic nicotinic receptors (nAChRs) located on GABAergic interneurons (GINs) are equally critical. One demonstration is that CINs stimulation induces large disynaptic inhibition of SPNs mediated by nAChR activation of striatal GINs. While these circuits are ideally positioned to modulate striatal output activity, the neurons involved are not definitively identified due largely to an incomplete mapping of CINs-GINs interconnections. Here, we show that CINs optogenetic activation evokes an intricate dual mechanism involving co-activation of pre- and postsynaptic mAChRs and nAChRs on four GINs populations. Using multi-optogenetics, we demonstrate the participation of tyrosine hydroxylase-expressing GINs in the disynaptic inhibition of SPNs likely via heterotypic electrical coupling with neurogliaform interneurons. Altogether, our results highlight the importance of CINs in regulating GINs microcircuits via complex synaptic/heterosynaptic mechanisms.

neuroscience↗