Lever-pressing Task Research Articles

The differential effect of optogenetic serotonergic manipulation on sustained motor actions and waiting for future rewards in mice.

Serotonin is an essential neuromodulator that affects behavioral and cognitive functions. Previous studies have shown that activation of serotonergic neurons in the dorsal raphe nucleus (DRN) promotes patience to wait for future rewards. However, it is still unclear whether serotonergic neurons also regulate persistence to act for future rewards. Here we used optogenetic activation and inhibition of DRN serotonergic neurons to examine their effects on sustained motor actions for future rewards. We trained mice to perform waiting and repeated lever-pressing tasks with variable reward delays and tested effects of optogenetic activation and inhibition of DRN serotonergic neurons on task performance. Interestingly, in the lever-pressing task, mice tolerated longer delays as they repeatedly pressed a lever than in the waiting task, suggesting that lever-pressing actions may not simply be costly, but may also be subjectively rewarding. Optogenetic activation of DRN serotonergic neurons prolonged waiting duration in the waiting task, consistent with previous studies. However, its effect on lever presses was nuanced, and was detected only by focusing on the period before premature reward check and by subtracting the trends within and across sessions using generalized linear model. While optogenetic inhibition decreased waiting, it did not affect lever pressing time or numbers. These results revealed that the necessity of motor actions may increase motivation for delayed rewards and that DRN serotonergic neurons more significantly promote waiting rather than persistent motor actions for future rewards.

Encoding of self-initiated actions in axon terminals of the mesocortical pathway.

The initiation of goal-directed actions is a complex process involving the medial prefrontal cortex and dopaminergic inputs through the mesocortical pathway. However, it is unclear what information the mesocortical pathway conveys and how it impacts action initiation. In this study, we unveiled the indispensable role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. To investigate the role of mesocortical axon terminals in encoding the execution of movements in self-initiated actions. We designed a lever-press task in which mice internally determine the timing of the press, receiving a larger reward for longer waiting periods. Our study revealed that self-initiated actions depend on dopaminergic signaling mediated by D2 receptors, whereas sensory-triggered lever-press actions do not involve D2 signaling. Microprism-mediated two-photon calcium imaging further demonstrated ramping activity in mesocortical axon terminals approximately 0.5s before the self-initiated lever press. Remarkably, the ramping patterns remained consistent whether the mice responded to cues immediately for a smaller reward or held their response for a larger reward. We conclude that mesocortical dopamine axon terminals encode the timing of self-initiated actions, shedding light on a crucial aspect of the intricate neural mechanisms governing goal-directed behavior.

A reinforcement learning model with choice traces for a progressive ratio schedule.

The progressive ratio (PR) lever-press task serves as a benchmark for assessing goal-oriented motivation. However, a well-recognized limitation of the PR task is that only a single data point, known as the breakpoint, is obtained from an entire session as a barometer of motivation. Because the breakpoint is defined as the final ratio of responses achieved in a PR session, variations in choice behavior during the PR task cannot be captured. We addressed this limitation by constructing four reinforcement learning models: a simple Q-learning model, an asymmetric model with two learning rates, a perseverance model with choice traces, and a perseverance model without learning. These models incorporated three behavioral choices: reinforced and non-reinforced lever presses and void magazine nosepokes, because we noticed that male mice performed frequent magazine nosepokes during PR tasks. The best model was the perseverance model, which predicted a gradual reduction in amplitudes of reward prediction errors (RPEs) upon void magazine nosepokes. We confirmed the prediction experimentally with fiber photometry of extracellular dopamine (DA) dynamics in the ventral striatum of male mice using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRABDA2m). We verified application of the model by acute intraperitoneal injection of low-dose methamphetamine (METH) before a PR task, which increased the frequency of magazine nosepokes during the PR session without changing the breakpoint. The perseverance model captured behavioral modulation as a result of increased initial action values, which are customarily set to zero and disregarded in reinforcement learning analysis. Our findings suggest that the perseverance model reveals the effects of psychoactive drugs on choice behaviors during PR tasks.

Frequency Specific Optogenetic Stimulation of the Locus Coeruleus Induces Task-Relevant Plasticity in the Motor Cortex.

The locus ceruleus (LC) is the primary source of neocortical noradrenaline, which is known to be involved in diverse brain functions including sensory perception, attention, and learning. Previous studies have shown that LC stimulation paired with sensory experience can induce task-dependent plasticity in the sensory neocortex and in the hippocampus. However, it remains unknown whether LC activation similarly impacts neural representations in the agranular motor cortical regions that are responsible for movement planning and production. In this study, we test whether optogenetic stimulation of the LC paired with motor performance is sufficient to induce task-relevant plasticity in the somatotopic cortical motor map. Male and female TH-Cre + rats were trained on a skilled reaching lever-pressing task emphasizing the use of the proximal forelimb musculature, and a viral approach was used to selectively express ChR2 in noradrenergic LC neurons. Once animals reached criterial behavioral performance, they received five training sessions in which correct task performance was paired with optogenetic stimulation of the LC delivered at 3, 10, or 30 Hz. After the last stimulation session, motor cortical mapping was performed using intracortical microstimulation. Our results show that lever pressing paired with LC stimulation at 10 Hz, but not at 3 or 30 Hz, drove the expansion of the motor map representation of the task-relevant proximal FL musculature. These findings demonstrate that phasic, training-paired activation of the LC is sufficient to induce experience-dependent plasticity in the agranular motor cortex and that this LC-driven plasticity is highly dependent on the temporal dynamics of LC activation.

Acute minocycline treatment inhibits microglia activation, reduces infarct volume, and has domain-specific effects on post-ischemic stroke cognition in rats

Ischemic stroke affects millions of individuals worldwide and a high prevalence of survivors experience cognitive deficits. At present, the underlying mechanisms that drive post-stroke cognitive decline are not well understood. Microglia play a critical role in the post-stroke inflammatory response, but experimental studies show that an accumulation of chronically activated microglia can be harmful and associates with cognitive impairment. This study assessed the effect of acute post-stroke minocycline treatment on chronic microglia and astrocyte expression within the infarct and remote white matter regions, as well as its effect on various domains of cognitive function post-stroke. Nine-month-old male rats received an injection of endothelin-1 into the right dorsal striatum to induce transient focal ischemia, and then were treated with minocycline or saline for 4 days post-stroke. Rats were tested using a series of lever-pressing tasks and the Morris water maze to assess striatal-based learning, cognitive flexibility, and spatial learning and reference memory. We found that minocycline-treated rats had smaller stroke-induced infarcts and less microglia activation in the infarct area and remote white matter regions compared to saline-treated rats at 28 days post-stroke. The behavioural testing results differed according to the cognitive domain; whereas minocycline-treated rats trended towards improved striatal-based learning in a lever-pressing task, but cognitive flexibility was unaffected during the subsequent set-shifting task. Furthermore, minocycline treatment unexpectedly impaired spatial learning, yet it did not alter reference memory. Collectively, we show that post-stroke minocycline treatment can reduce chronic microglia activation even in remote brain regions, with domain-specific effects on cognitive function.

Motor cortex projections to red and pontine nuclei have distinct roles during movement in the mouse

Motor control largely depends on the deep layer 5 (L5) pyramidal neurons that project to subcortical structures. However, it is largely unknown if these neurons are functionally segregated with distinct roles in movement performance. Here, we analyzed mouse motor cortex L5 pyramidal neurons projecting to the red and pontine nuclei during movement preparation and execution. Using photometry to analyze the calcium activity of L5 pyramidal neurons projecting to the red nucleus and pons, we reveal that both types of neurons activate with different temporal dynamics. Optogenetic inhibition of either kind of projection differentially affects forelimb movement onset and execution in a lever press task, but only the activity of corticopontine neurons is significantly correlated with trial-by-trial variations in reaction time. The results indicate that cortical neurons projecting to the red and pontine nuclei contribute differently to sensorimotor integration, suggesting that L5 output neurons are functionally compartmentalized generating, in parallel, different downstream information.

Slow-rising and fast-falling dopaminergic dynamics jointly adjust negative prediction error in the ventral striatum.

The greater the reward expectations are, the more different the brain's physiological response will be. Although it is well-documented that better-than-expected outcomes are encoded quantitatively via midbrain dopaminergic (DA) activity, it has been less addressed experimentally whether worse-than-expected outcomes are expressed quantitatively as well. We show that larger reward expectations upon unexpected reward omissions are associated with the preceding slower rise and following larger decrease (DA dip) in the DA concentration at the ventral striatum of mice. We set up a lever press task on a fixed ratio (FR) schedule requiring five lever presses as an effort for a food reward (FR5). The mice occasionally checked the food magazine without a reward before completing the task. The percentage of this premature magazine entry (PME) increased as the number of lever presses approached five, showing rising expectations with increasing proximity to task completion, and hence greater reward expectations. Fibre photometry of extracellular DA dynamics in the ventral striatum using a fluorescent protein (genetically encoded GPCR activation-based DA sensor: GRABDA2m ) revealed that the slow increase and fast decrease in DA levels around PMEs were correlated with the PME percentage, demonstrating a monotonic relationship between the DA dip amplitude and degree of expectations. Computational modelling of the lever press task implementing temporal difference errors and state transitions replicated the observed correlation between the PME frequency and DA dip amplitude in the FR5 task. Taken together, these findings indicate that the DA dip amplitude represents the degree of reward expectations monotonically, which may guide behavioural adjustment.

Corticospinal neurons from motor and somatosensory cortices exhibit different temporal activity dynamics during motor learning.

The ability to learn motor skills implicates an improvement in accuracy, speed and consistency of movements. Motor control is related to movement execution and involves corticospinal neurons (CSp), which are broadly distributed in layer 5B of the motor and somatosensory cortices. CSp neurons innervate the spinal cord and are functionally diverse. However, whether CSp activity differs between different cortical areas throughout motor learning has been poorly explored. Given the importance and interaction between primary motor (M1) and somatosensory (S1) cortices related to movement, we examined the functional roles of CSp neurons in both areas. We induced the expression of GCaMP7s calcium indicator to perform photometric calcium recordings from layer 5B CSp neurons simultaneously in M1 and S1 cortices and track their activity while adult mice learned and performed a cued lever-press task. We found that during early learning sessions, the population calcium activity of CSp neurons in both cortices during movement did not change significantly. In late learning sessions the peak amplitude and duration of calcium activity CSp neurons increased in both, M1 and S1 cortices. However, S1 and M1 CSp neurons display a different temporal dynamic during movements that occurred when animals learned the task; both M1 and S1 CSp neurons activate before movement initiation, however, M1 CSp neurons continue active during movement performance, reinforcing the idea of the diversity of the CSp system and suggesting that CSp neuron activity in M1 and S1 cortices throughout motor learning have different functional roles for sensorimotor integration.

Extracting synchronized neuronal activity from local field potentials based on a marked point process framework

Objective. Brain-machine interfaces (BMIs) translate neural activity into motor commands to restore motor functions for people with paralysis. Local field potentials (LFPs) are promising for long-term BMIs, since the quality of the recording lasts longer than single neuronal spikes. Inferring neuronal spike activity from population activities such as LFPs is challenging, because LFPs stem from synaptic currents flowing in the neural tissue produced by various neuronal ensembles and reflect neural synchronization. Existing studies that combine LFPs with spikes leverage the spectrogram of the former, which can neither detect the transient characteristics of LFP features (here, neuromodulation in a specific frequency band) with high accuracy, nor correlate them with relevant neuronal activity with a sufficient time resolution. Approach. We propose a feature extraction and validation framework to directly extract LFP neuromodulations related to synchronized spike activity using recordings from the primary motor cortex of six Sprague Dawley rats during a lever-press task. We first select important LFP frequency bands relevant to behavior, and then implement a marked point process (MPP) methodology to extract transient LFP neuromodulations. We validate the LFP feature extraction by examining the correlation with the pairwise synchronized firing probability of important neurons, which are selected according to their contribution to behavioral decoding. The highly correlated synchronized firings identified by the LFP neuromodulations are fed into a decoder to check whether they can serve as a reliable neural data source for movement decoding. Main results. We find that the gamma band (30–80 Hz) LFP neuromodulations demonstrate significant correlation with synchronized firings. Compared with traditional spectrogram-based method, the higher-temporal resolution MPP method captures the synchronized firing patterns with fewer false alarms, and demonstrates significantly higher correlation than single neuron spikes. The decoding performance using the synchronized neuronal firings identified by the LFP neuromodulations can reach 90% compared to the full recorded neuronal ensembles. Significance. Our proposed framework successfully extracts the sparse LFP neuromodulations that can identify temporal synchronized neuronal spikes with high correlation. The identified neuronal spike pattern demonstrates high decoding performance, which suggest LFP can be used as an effective modality for long-term BMI decoding.

Global and subtype-specific modulation of cortical inhibitory neurons regulated by acetylcholine during motor learning

Inhibitory neurons (INs) consist of distinct subtypes with unique functions. Previous studies on INs mainly focused on single brain regions, and thus it remains unclear whether the modulation of IN subtypes occurs globally across multiple regions. Here, we monitored the activity of different cortical IN subtypes at both macroscale and microscale in mice learning a lever-press task. Learning evoked a global modulation of IN subtypes throughout the cortex. The initial learning phase involved strong activation of vasoactive intestinal peptide-expressing INs (VIP-INs) and weak activation of somatostatin-expressing INs (SOM-INs). Inactivating VIP-INs increased SOM-IN activity and impaired initial learning. Concurrently, cortical cholinergic inputs from the basal forebrain were initially more active but became less engaged over learning. Manipulation of the cholinergic system impaired motor learning and differentially altered activity of IN subtypes. These results reveal that motor learning involves a global and subtype-specific modulation on cortical INs regulated by the cholinergic system.

Automated lever task with minimum antigravity movement for rats with cervical spinal cord injury

BackgroundAlthough there is currently no cure for paralysis due to spinal cord injury (SCI), the highest treatment priority is restoring arm and hand function for people with cervical SCI. Preclinical animal models provide an opportunity to test innovative treatments, but severe cervical injury models require significant time and effort to assess responses to novel interventions. Moreover, there is no behavioral task that can assess forelimb movement in rats with severe cervical SCI unable to perform antigravity movements. New methodWe developed a novel lever pressing task for rats with severe cervical SCI. We employed an automated adaptive algorithm to train animals using open-source software and commercially available hardware. We found that using the adaptive training required only 13.3 ± 2.5 training days to achieve behavioral proficiency. The lever press task could quantify immediate and long-term improvements in severely impaired forelimb function effectively. This behavior platform has potential to facilitate rehabilitative training and assess effects of therapeutic modalities following SCI. Comparison with existing methodsThere is no existing assessment aiming to quantify forelimb extension movement in rodents without function against gravity. We found that the new lever press task in the antigravity position could assess the severity of cervical SCI as well as the compensatory movement in the proximal forelimb less affected by the injury. ConclusionsThis study demonstrates that the new behavioral task is capable of tracking the functional changes with various therapies in rats with severe forelimb impairments in a cost- and time-efficient manner.

Online Decoding System with Calcium Image From Mice Primary Motor Cortex.

With the development of calcium imaging, neuroscientists have been able to study neural activity with a higher spatial resolution. However, the real-time processing of calcium imaging is still a big challenge for future experiments and applications. Most neuroscientists have to process their imaging data offline due to the time-consuming of most existing calcium imaging analysis methods. We proposed a novel online neural signal processing framework for calcium imaging and established an Optical Brain-Computer Interface System (OBCIs) for decoding neural signals in real-time. We tested and evaluated this system by classifying the calcium signals obtained from the primary motor cortex of mice when the mice were performing a lever-pressing task. The performance of our online system could achieve above 80% in the average decoding accuracy. Our preliminary results show that the online neural processing framework could be applied to future closed-loop OBCIs studies.

Vagus Nerve Stimulation Induced Motor Map Plasticity Does Not Require Cortical Dopamine.

Background: Vagus nerve stimulation (VNS) paired with motor rehabilitation is an emerging therapeutic strategy to enhance functional recovery after neural injuries such as stroke. Training-paired VNS drives significant neuroplasticity within the motor cortex (M1), which is thought to underlie the therapeutic effects of VNS. Though the mechanisms are not fully understood, VNS-induced cortical plasticity is known to depend on intact signaling from multiple neuromodulatory nuclei that innervate M1. Cortical dopamine (DA) plays a key role in mediating M1 synaptic plasticity and is critical for motor skill acquisition, but whether cortical DA contributes to VNS efficacy has not been tested.Objective: To determine the impact of cortical DA depletion on VNS-induced cortical plasticity.Methods: Rats were trained on a skilled reaching lever press task prior to implantation of VNS electrodes and 6-hydroxydopamine (6-OHDA) mediated DA depletion in M1. Rats then underwent training-paired VNS treatment, followed by cortical motor mapping and lesion validation.Results: In both intact and DA-depleted rats, VNS significantly increased the motor map representation of task-relevant proximal forelimb musculature and reduced task-irrelevant distal forelimb representations. VNS also significantly increased tyrosine hydroxylase (TH+) fiber density in intact M1, but this effect was not observed in lesioned hemispheres.Conclusion: Our results reveal that though VNS likely upregulates catecholaminergic signaling in intact motor cortices, DA itself is not required for VNS-induced plasticity to occur. As DA is known to critically support M1 plasticity during skill acquisition, our findings suggest that VNS may engage a unique set of neuromodulatory signaling pathways to promote neocortical plasticity.

Hierarchical Dynamical Model for Multiple Cortical Neural Decoding.

Motor brain machine interfaces (BMIs) interpret neural activities from motor-related cortical areas in the brain into movement commands to control a prosthesis. As the subject adapts to control the neural prosthesis, the medial prefrontal cortex (mPFC), upstream of the primary motor cortex (M1), is heavily involved in reward-guided motor learning. Thus, considering mPFC and M1 functionality within a hierarchical structure could potentially improve the effectiveness of BMI decoding while subjects are learning. The commonly used Kalman decoding method with only one simple state model may not be able to represent the multiple brain states that evolve over time as well as along the neural pathway. In addition, the performance of Kalman decoders degenerates in heavy-tailed nongaussian noise, which is usually generated due to the nonlinear neural system or influences of movement-related noise in online neural recording. In this letter, we propose a hierarchical model to represent the brain states from multiple cortical areas that evolve along the neural pathway. We then introduce correntropy theory into the hierarchical structure to address the heavy-tailed noise existing in neural recordings. We test the proposed algorithm on in vivo recordings collected from the mPFC and M1 of two rats when the subjects were learning to perform a lever-pressing task. Compared with the classic Kalman filter, our results demonstrate better movement decoding performance due to the hierarchical structure that integrates the past failed trial information over multisite recording and the combination with correntropy criterion to deal with noisy heavy-tailed neural recordings.

Chronic social defeat stress impairs goal-directed behavior through dysregulation of ventral hippocampal activity in male mice

Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.

Differential Plasticity in Auditory and Prefrontal Cortices, and Cognitive-Behavioral Deficits Following Noise-Induced Hearing Loss

Excessive exposure to loud noise causes hearing loss and neural plasticity throughout the auditory pathway. Recent studies have identified that non-auditory regions, such as the hippocampus, are also susceptible to noise exposure; however, the electrophysiological and behavioral consequences of noise-induced hearing loss on the prefrontal cortex (PFC) are unclear. Using chronically-implanted electrodes in awake rats, we investigated neural plasticity in the auditory and prefrontal cortices in the days following noise exposure via metrics associated with spontaneous neural oscillations and the 40-Hz auditory steady-state response (ASSR). Noise exposure did not alter the profile of spontaneous oscillations in either of the cortices, yet it caused a differential plasticity in the sound-evoked activity, which was characterized by enhanced event-related potentials (ERPs) in the auditory cortex (i.e., central gain), and decreased inter-trial coherence (ITC) of the 40-Hz ASSR within the PFC. Moreover, phase synchrony between auditory and prefrontal cortices was decreased post-exposure, suggesting a reduction in functional connectivity. Cognitive-behavioral testing using the Morris water maze and a series of lever-pressing tasks revealed that noise exposure impaired spatial learning and reference memory, as well as stimulus–response habit learning, whereas cognitive flexibility tasks requiring set-shifting and reversal learning appeared unaffected. Collectively, our findings identify the complex and region-specific cortical plasticity associated with noise-induced hearing loss, and highlight the varying degrees of susceptibility of non-auditory, cognitive tasks of learning, memory and executive function to noise exposure.

Stability of motor cortex network states during learning-associated neural reorganizations.

A substantial reorganization of neural activity and neuron-to-movement relationship in motor cortical circuits accompanies the emergence of reproducible movement patterns during motor learning. Little is known about how this tempest of neural activity restructuring impacts the stability of network states in recurrent cortical circuits. To investigate this issue, we reanalyzed data in which we recorded for 14 days via population calcium imaging the activity of the same neural populations of pyramidal neurons in layer 2/3 and layer 5 of forelimb motor and premotor cortex in mice during the daily learning of a lever-press task. We found that motor cortex network states remained stable with respect to the critical network state during the extensive reorganization of both neural population activity and its relation to lever movement throughout learning. Specifically, layer 2/3 cortical circuits unceasingly displayed robust evidence for operating at the critical network state, a regime that maximizes information capacity and transmission and provides a balance between network robustness and flexibility. In contrast, layer 5 circuits operated away from the critical network state for all 14 days of recording and learning. In conclusion, this result indicates that the wide-ranging malleability of synapses, neurons, and neural connectivity during learning operates within the constraint of a stable and layer-specific network state regarding dynamic criticality, and suggests that different cortical layers operate under distinct constraints because of their specialized goals.NEW & NOTEWORTHY The neural activity reorganizes throughout motor learning, but how this reorganization impacts the stability of network states is unclear. We used two-photon calcium imaging to investigate how the network states in layer 2/3 and layer 5 of forelimb motor and premotor cortex are modulated by motor learning. We show that motor cortex network states are layer-specific and constant regarding criticality during neural activity reorganization, and suggests that layer-specific constraints could be motivated by different functions.

Vagus nerve stimulation promotes cortical reorganization and reduces task-dependent calorie intake in male and female rats

Numerous preclinical studies demonstrate that vagus nerve stimulation (VNS) paired with motor rehabilitation improves functional recovery after neural injuries such as stroke, traumatic brain injury, and spinal cord injury, in part by driving neural plasticity within the motor cortex. To date, these studies have been performed almost exclusively in female rats, however, the risk for neural injuries of all types is significantly higher among males than females. We therefore sought to determine whether VNS was equally effective at driving motor cortical plasticity in both sexes. Male and female rats were trained on a skilled lever press task prior to VNS electrode implantation. After recovery, rats received ten training sessions in which VNS, or sham stimulation, was paired with correct motor performance. At the completion of these treatment sessions, somatotopic mapping of motor cortex was performed. We found that performance on the lever task was similar between male and female rats, though on average, males performed more trials per training session, consistent with their larger size and higher caloric need. Training-paired VNS effectively induced cortical motor map reorganization in both male and female rats. Notably, we also found that VNS reduced lever-press associated caloric intake during treatment in both sexes. These VNS-driven effects were robust to behavioral and biological differences between male and female subjects. Taken together, our results suggest that, in both male and female rats, VNS simultaneously engages both pro-plasticity neuromodulation within the neocortex and satiety or reward-related networks that reduce task-associated caloric intake.

Chemogenetic Modulation and Single-Photon Calcium Imaging in Anterior Cingulate Cortex Reveal a Mechanism for Effort-Based Decisions.

The ACC is implicated in effort exertion and choices based on effort cost, but it is still unclear how it mediates this cost-benefit evaluation. Here, male rats were trained to exert effort for a high-value reward (sucrose pellets) in a progressive ratio lever-pressing task. Trained rats were then tested in two conditions: a no-choice condition where lever-pressing for sucrose was the only available food option, and a choice condition where a low-value reward (lab chow) was freely available as an alternative to pressing for sucrose. Disruption of ACC, via either chemogenetic inhibition or excitation, reduced lever-pressing in the choice, but not in the no-choice, condition. We next looked for value coding cells in ACC during effortful behavior and reward consumption phases during choice and no-choice conditions. For this, we used in vivo miniaturized fluorescence microscopy to reliably track responses of the same cells and compare how ACC neurons respond during the same effortful behavior where there was a choice versus when there was no-choice. We found that lever-press and sucrose-evoked responses were significantly weaker during choice compared with no-choice sessions, which may have rendered them more susceptible to chemogenetic disruption. Together, findings from our interference experiments and neural recordings suggest that a mechanism by which ACC mediates effortful decisions is in the discrimination of the utility of available options. ACC regulates these choices by providing a stable population code for the relative value of different options.SIGNIFICANCE STATEMENT The ACC is implicated in effort-based decision-making. Here, we used chemogenetics and in vivo calcium imaging to explore its mechanism. Rats were trained to lever press for a high-value reward and tested in two conditions: a no-choice condition where lever-pressing for the high-value reward was the only option, and a choice condition where a low-value reward was also available. Inhibition or excitation of ACC reduced effort toward the high-value option, but only in the choice condition. Neural responses in ACC were weaker in the choice compared with the no-choice condition. A mechanism by which ACC regulates effortful decisions is in providing a stable population code for the discrimination of the utility of available options.

Opposing Ventral Striatal Medium Spiny Neuron Activities Shaped by Striatal Parvalbumin-Expressing Interneurons during Goal-Directed Behaviors

Medium spiny neurons (MSNs) of mice show opposing activities upon the initiation of a food-seeking lever press task. Ventromedial striatal (VMS)-MSNs are inhibited but ventrolateral striatal (VLS)-MSNs are activated; these activities mediate action selection and action initiation, respectively. To understand what input shapes the opposing MSN activities, here, we monitor cortical input activities at the cell population level and artificially reverse them. We demonstrate that the ventral hippocampus (vHP) and the insular cortex (IC) are major inputs to the VMS and VLS, both projections show silencing at the trial start time, and the vHP-VMS and IC-VLS pathways form functionally coupled input-output units during the task. Of note, the upstream IC silencing is converted to the downstream VLS-MSN activation. We find biased localization of striatal parvalbumin-expressing interneurons (PV INs) and verify PV IN-dependent feedforward architecture in the VLS. Our results reveal a distinct mode of cortico-striatal signal conveyance via feedforward disinhibition in behaving animals.