Biology subjects

Mohebi, A.

Publications and source records attributed to Mohebi, A..

8 recordsLinked to original sources

bioRxiv2024

A mismatch between striatal cholinergic pauses and dopaminergic reward prediction errors

Movement, motivation and reward-related learning depend strongly on striatal dopamine and acetylcholine. These neuromodulators each regulate the other, and disturbances to their coordinated signals contribute to human disorders ranging from Parkinsons Disease to depression and addiction. Pauses in the firing of cholinergic interneurons (CINs) are thought to coincide with pulses in dopamine release that encode reward prediction errors (RPEs), together shaping synaptic plasticity and thereby learning. However, such models are based upon recordings from unidentified neurons, and do not incorporate the distinct characteristics of striatal subregions. Here we compare the firing of identified, individual CINs to dopamine release as unrestrained rats performed a probabilistic decision-making task. The relationships between CIN spiking, dopamine release, and behavior varied strongly by subregion. In dorsal-lateral striatum a Go! cue evoked burst-pause CIN spiking, quickly followed by a very brief (~150ms) dopamine pulse that was unrelated to RPE. In dorsal-medial striatum the same cue evoked only a CIN pause; this pause was curtailed by a movement-selective rebound in firing. Finally in ventral striatum a reward cue evoked slower, RPE-coding increases in both dopamine and CIN firing, without any distinct pause. Our results demonstrate a spatial and temporal dissociation between CIN pauses and dopamine RPE signals, and will inform new models of striatal microcircuits and their contributions to behavior.

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bioRxiv2024

Mesolimbic dopamine ramps reflect environmental timescales

Mesolimbic dopamine activity occasionally exhibits ramping dynamics, reigniting debate on theories of dopamine signaling. This debate is ongoing partly because the experimental conditions under which dopamine ramps emerge remain poorly understood. Here, we show that during Pavlovian and instrumental conditioning, mesolimbic dopamine ramps are only observed when the inter-trial interval is short relative to the trial period. These results constrain theories of dopamine signaling and identify a critical variable determining the emergence of dopamine ramps.

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bioRxiv2023

Comment on 'Accumbens cholinergic interneurons dynamically promote dopamine release and enable motivation'

Acetylcholine is widely believed to modulate the release of dopamine in the striatum of mammals. Experiments in brain slices clearly show that synchronous activation of striatal cholinergic interneurons is sufficient to drive dopamine release via axo-axonal stimulation of nicotinic acetylcholine receptors. However, evidence for this mechanism in vivo has been less forthcoming. A recent paper in eLife (Mohebi et al., 2023) reported that, in awake behaving rats, optogenetic activation of striatal cholinergic interneurons with blue light readily evokes dopamine release measured with the red fluorescent sensor RdLight1. Here, we show that blue light alone alters the fluorescent properties of RdLight1 in a manner that may be misconstrued as phasic dopamine release, and that this artefactual photoactivation can account for the effects attributed to cholinergic interneurons. Our findings indicate that measurements of dopamine using the red-shifted fluorescent sensor RdLight1 should be interpreted with caution when combined with optogenetics. In light of this and other publications that did not observe large acetylcholine-evoked dopamine transients in vivo, the conditions under which such release occurs in behaving animals remain unknown.

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bioRxiv2023

Reward expectation selectively boosts the firing of accumbens D1+ neurons during motivated approach.

The nucleus accumbens (NAc) helps govern motivation to pursue rewards. Two distinct sets of NAc projection neurons-expressing dopamine D1 versus D2 receptors-are thought to promote and suppress motivated behaviors respectively. However, support for this conceptual framework is limited: in particular the spiking patterns of these distinct cell types during motivated behavior have been largely unknown. We monitored identified D1+ and D2+ neurons in the NAc Core, as unrestrained rats performed an operant task in which motivation to initiate work tracks recent reward rate. D1+ neurons preferentially increased firing as rats initiated trials, and fired more when reward expectation was higher. By contrast, D2+ cells preferentially increased firing later in the trial especially in response to reward delivery - a finding not anticipated from current theoretical models. Our results provide new evidence for the specific contribution of NAc D1+ cells to self-initiated approach behavior, and will spur updated models of how we learn from rewards.

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bioRxiv2022

Cholinergic Interneurons Drive Motivation by Promoting Dopamine Release in the Nucleus Accumbens

Motivation to work for potential rewards is critically dependent on dopamine (DA) in the nucleus accumbens (NAc). DA release from NAc axons can be controlled by at least two distinct mechanisms: 1) action potentials propagating from DA cell bodies in the ventral tegmental area (VTA), and 2) activation of {beta}2* nicotinic receptors by local cholinergic interneurons (CINs). How CIN activity contributes to NAc DA dynamics in behaving animals remains unclear. We monitored DA release in the NAc Core of awake, unrestrained rats while simultaneously monitoring or manipulating CIN activity at the same location. CIN stimulation rapidly evoked DA release, and in contrast to slice preparations, this DA release showed no indication of short-term depression or receptor desensitization. The sound of food delivery evoked a brief joint increase in CIN population activity and DA release, with a second joint increase as rats approached the food. In an operant task, we observed fast ramps in CIN activity during approach behaviors, either to start the trial or to collect rewards. These CIN ramps co-occurred with DA release ramps, without corresponding changes in the firing of VTA DA neurons. Finally, we examined the effects of blocking CIN influence over DA release through local NAc infusion of DH{beta}E, a selective antagonist of [Formula] nicotinic receptors. DH{beta}E dose-dependently interfered with motivated approach decisions, mimicking the effects of a DA antagonist. Our results support a key influence of CINs over motivated behavior via the local regulation of DA release.

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bioRxiv2021

Striatal dopamine pulses follow a temporal discounting spectrum

Dopamine input to striatum can encode reward prediction error, a critical signal for updating predictions of future rewards. However, it is unclear how this mechanism handles the need to make predictions, and provide feedback, over multiple time horizons: from seconds or less (if singing a song) to potentially hours or more (if hunting for food). Here we report that dopamine pulses in distinct striatal subregions convey reward prediction errors over distinct temporal scales. Dopamine dynamics systematically accelerated from ventral to dorsal-medial to dorsal-lateral striatum, in the tempo of their spontaneous fluctuations, their integration of prior rewards, and their discounting of future rewards. This spectrum of time scales for value computations can help achieve efficient learning and adaptive motivation for a wide range of behaviors.

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bioRxiv2020

Lateralized role of prefrontal cortex in guiding orienting behavior

Orienting movements are essential to sensory-guided reward-seeking behaviors. Prefrontal cortex (PFC) is believed to exert top-down control over a range of goal-directed behaviors and is hypothesized to bias sensory-guided movements. However, the nature of PFC involvement in controlling sensory-guided orienting behaviors has remained largely unknown. Here, we trained rats on a delayed two-alternative forced-choice task requiring them to hold an orienting decision in working memory before execution is cued. Medial PFC (mPFC) Inactivation using either Muscimol or optogenetics impaired choice behavior. However, optogenetic impairment depended on the specific trial epoch during which inactivation took place. In particular, we found a lateralized role for mPFC during the presentation of instruction cues but this role became bilateral when inactivation occurred later in the delay period. Electrophysiological recording of multiple single-unit activity further provided evidence that this lateralized selectivity is cell-type specific. Our results suggest a previously unknown role of mPFC in mediating sensory-guided representation of orienting behavior and a potentially distinct cell-type specific role in shaping such representation across time.

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bioRxiv2018

Forebrain dopamine value signals arise independently from midbrain dopamine cell firing.

The mesolimbic dopamine projection from the ventral tegmental area (VTA) to nucleus accumbens (NAc) is a key pathway for reward-driven learning, and for the motivation to work for more rewards. VTA dopamine cell firing can encode reward prediction errors (RPEs1,2), vital learning signals in computational theories of adaptive behavior. However, NAc dopamine release more closely resembles reward expectation (value), a motivational signal that invigorates approach behaviors3-7. This discrepancy might be due to distinct behavioral contexts: VTA dopamine cells have been recorded under head-fixed conditions, while NAc dopamine release has been measured in actively-moving subjects. Alternatively the mismatch may reflect changes in the tonic firing of dopamine cells8, or a fundamental dissociation between firing and release. Here we directly compare dopamine cell firing and release in the same adaptive decision-making task. We show that dopamine release covaries with reward expectation in two specific forebrain hotspots, NAc core and ventral prelimbic cortex. Yet the firing rates of optogenetically-identified VTA dopamine cells did not correlate with reward expectation, but instead showed transient, error-like responses to unexpected cues. We conclude that critical motivation-related dopamine dynamics do not arise from VTA dopamine cell firing, and may instead reflect local influences over forebrain dopamine varicosities.

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