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Zuelke, D. R.

Publications and source records attributed to Zuelke, D. R..

4 recordsLinked to original sources

Nucleus accumbens acetylcholine dips track reward value and temporal costs to shape delay discounting

As an organism chooses between competing rewards, it must often integrate learned reward value with the changing costs associated with obtaining them. Yet, the brain mechanisms through which these factors jointly guide choice are not well understood. Previous studies have shown that dopamine signals in the nucleus accumbens (NAc) track reward value and are modulated by their associated delay costs. Our prior work further implicated NAc cholinergic interneurons by demonstrating that dopamine D2 receptors in these neurons influence choice under temporal, but not probabilistic, costs. However, whether NAc acetylcholine (ACh) dynamics track reward value and/or delay, and whether they contribute to adaptive choice, remains unknown. Using in vivo fiber photometry during a delay discounting task in which mice choose between a small, immediate reward and a larger, delayed reward, we reveal that cue-evoked ACh dips dynamically track relative reward magnitude and are diminished by increasing delays. Our data further show that optogenetically enhancing these dips attenuates the delay-dependent decline in choice of the larger, delayed reward. These findings identify a previously unrecognized role for NAc cue-evoked ACh dips in shaping adaptive choice as temporal costs increase.

neuroscience↗

Ventral Pallidum Cholinergic Neurons Respond to Reward and Signal Reward Value

The ventral pallidum (VP) is a key basal ganglia structure involved in integrating reward-related signals to guide motivated behavior and feeding. VP neuronal activity is strongly tuned to reward-predictive cues and palatable rewards, tracking changes in value and motivational state. Recent studies have established important and opposing roles for GABAergic and glutamatergic VP neurons in reward- and avoidance-related behaviors. However, much less is known about the role of VP cholinergic neurons (VP-CNs), which comprise only [~]10% of VP neurons in mice, but maintain extensive connectivity with reward-related circuitry. Here, using cell type-selective in vivo fiber photometry during instrumental reward behavior, we found that VP-CN activity responds to cues, actions, and reward retrieval in a training-independent manner. Phasic VP-CN responses to reward retrieval were reduced by reward dilution, whereas pre-feeding with the reward enhanced these responses. In contrast, non-cholinergic VP neurons exhibited modulation by pre-feeding but not by reward dilution. Together, these findings identify VP-CNs as a distinct and dynamically regulated VP population whose activity is sensitive to both reward palatability and physiological state, extending our current understanding of the VP and its roles in reward processing.

neuroscience↗

Expression of Angiotensin converting enzyme 2 (ACE2) in the dorsolateral striatum is critical for the temporal coordination of acetylcholine and dopamine, and motor learning.

Neuropeptides are key modulators of adult neurocircuits, balancing their sensitivity to both excitation and inhibition, and fine-tuning fast neurotransmitter action under physiological conditions. We found that the mono-carboxypeptidase angiotensin-converting enzyme 2 (ACE2), which can take part in producing and/or processing of several neuroactive peptides in the mammalian brain and is best known for converting the pro-inflammatory peptide angiotensin II (Ang II) to the stress-ameliorating and neuro-protective peptide angiotensin 1-7 (Ang 1-7), is broadly expressed in the striatum. Cholinergic interneurons (CIN) of the striatum, known to express multiple peptide receptors also co-expressed the corresponding and functionally opposing receptors angiotensin type 1 receptor (AT1R) for Ang II and mas receptor (MasR) for Ang 1-7. Accordingly, the conditional, semi acute ablation and/or local pharmacological inhibition of ACE2 increased the frequency of acetylcholine (ACh) bursts, reduced the amplitude of dopamine (DA)-modulated pausing of CIN activity, and disrupted the temporal coordination of extracellular levels of ACh and DA during burst events. Further, ablation of ACE2 in the DLS biased directional movement and impaired motor skill learning. Coinjection of the AT1R inhibitor losartan and the dopamine D2 receptor (D2R) agonist quinpirole reduced steady state level cholinergic activity in an additive manner, and proximity ligation supported close spatial association of AT1R and D2R on CINs. Together our study provides evidence that striatal produced ACE2 impinges on the dynamics of ACh and DA and impacts action selection and motor learning through functional and structural interactions of peptidergic and dopaminergic signaling on CIN. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/684469v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@13b6cf0org.highwire.dtl.DTLVardef@6d1ef1org.highwire.dtl.DTLVardef@a7e2eorg.highwire.dtl.DTLVardef@e22816_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

neuroscience↗

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Expression of Abnormal Involuntary Movements

L-Dopa induced dyskinesia (LID) is a debilitating side effect of dopamine replacement therapy for Parkinsons Disease. The mechanistic underpinnings of LID remain obscure. Here we report that diminshed sonic hedgehog (Shh) signaling in the basal ganglia caused by the degeneration of midbrain dopamine neurons (DANs) facilitates the formation and expression of LID. We demonstrate that augmenting Shh signaling with agonists of the Shh effector Smoothened attenuates LID in mouse and macaque models of PD. Employing conditional genetic loss-of-function approaches, we show that reducing Shh secretion from DANs or Smo activity in cholinergic interneurons (CINs) promotes LID. Conversely, the selective expression of constitutively active Smo (SmoM2) in CINs is sufficient to render the sensitized aphakia model of PD resistant to LID. Furthermore, acute depletion of Shh from DANs through prolonged optogenetic stimulation in otherwise intact mice and in the absence of L-Dopa produces LID-like involuntary movements. These findings indicate that augmenting Shh signaling in the L-Dopa treated brain may be a promising and unexpected novel therapeutic approach for mitigating the dyskinetic side effects of long-term treatment with L-Dopa

neuroscience↗