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Animals can learn to repeat behaviors to earn desired rewards, a process commonly known as reinforcement learning. While previous work has implicated the ascending dopaminergic projections to the basal ganglia in reinforcement learning, little is known about the role of the hippocampus. Here we report that a specific population of hippocampal neurons and their dopaminergic innervation contribute to operant self-stimulation. These neurons are located in the dentate gyrus, receive dopaminergic projections from the locus coeruleus, and express D1 dopamine receptors. Activation of D1+ dentate neurons is sufficient for self-stimulation: mice will press a lever to earn optogenetic activation of these neurons. A similar effect is also observed with selective activation of the locus coeruleus projections to the dentate gyrus, and blocked by D1 receptor antagonism. Calcium imaging of D1+ dentate neurons revealed significant activity at the time of action selection, but not during passive reward delivery. These results reveal the role of dopaminergic innervation of the hippocampus in supporting operant reinforcement.

Selective activation of Pf-STN pathway initiates actions in normal mice and restores movement in a mouse model of PD., The parafascicular nucleus (Pf) of the thalamus provides major projections to the basal ganglia, a set of subcortical nuclei involved in action initiation. Here, we show that Pf projections to the subthalamic nucleus (STN), but not to the striatum, are responsible for movement initiation. Because the STN is a major target of deep brain stimulation treatments for Parkinson’s disease, we tested the effect of selective stimulation of Pf-STN projections in a mouse model of PD. Bilateral dopamine depletion with 6-OHDA created complete akinesia in mice, but Pf-STN stimulation immediately and markedly restored a variety of natural behaviors. Our results therefore revealed a functionally novel neural pathway for the initiation of movements that can be recruited to rescue movement deficits after dopamine depletion. They not only shed light on the clinical efficacy of conventional STN DBS but also suggest more selective and improved stimulation strategies for the treatment of parkinsonian symptoms.

New memory formation depends on both the hippocampus and modulatory effects of acetylcholine. The mechanism by which acetylcholine levels in the hippocampus enable new encoding remains poorly understood. Here, we tested the hypothesis that cholinergic modulation supports memory formation by leading to structured spike timing in the hippocampus. Specifically, we tested if phase precession in dorsal CA1 was reduced under the influence of a systemic cholinergic antagonist. Unit and field potential were recorded from the dorsal CA1 of rats as they completed laps on a circular track for food rewards before and during the influence of the systemically administered acetylcholine muscarinic receptor antagonist scopolamine. We found that scopolamine significantly reduced phase precession of spiking relative to the field theta, and that this was due to a decrease in the frequency of the spiking rhythmicity. We also found that the correlation between position and theta phase was significantly reduced. This effect was not due to changes in spatial tuning as tuning remained stable for those cells analyzed. Similarly, it was not due to changes in lap‐to‐lap reliability of spiking onset or offset relative to either position or phase as the reliability did not decrease following scopolamine administration. These findings support the hypothesis that memory impairments that follow muscarinic blockade are the result of degraded spike timing in the hippocampus.

The contributions of cortico-cerebellar and cortico-striatal circuits to timing and time perception have often been a point of contention. In this review we propose that the cerebellum principally functions to reduce variability, through the detection of stimulus onsets and the sub-division of longer durations, thus contributing to both sub-second and supra-second timing. This sensitivity of the cerebellum to stimulus dynamics and subsequent integration with motor control allows it to accurately measure intervals within a range of 100–2000 ms. For intervals in the supra-second range (e.g., >2000 ms), we propose that cerebellar output signals from the dentate nucleus pass through thalamic connections to the striatum, where cortico-thalamic-striatal circuits supporting higher-level cognitive functions take over. Moreover, the importance of intrinsic circuit dynamics as well as behavioral, neuroimaging, and lesion studies of the cerebellum and striatum are discussed in terms of a framework positing initiation, continuation, adjustment, and termination phases of temporal processing.

Summary The ventral tegmental area (VTA) is a midbrain region implicated in a variety of motivated behaviors. However, the function of VTA GABAergic (Vgat+) neurons remains poorly understood. Here, using three-dimensional motion capture, in vivo electrophysiology, calcium imaging, and optogenetics, we demonstrate a novel function of VTAVgat+ neurons. We found three distinct populations of neurons, each representing head angle about a principal axis of rotation: yaw, roll, and pitch. For each axis, opponent cell groups were found that increase firing when the head moves in one direction and decrease firing in the opposite direction. Selective excitation and inhibition of VTAVgat+ neurons generate opposite rotational movements. Thus, VTAVgat+ neurons serve a critical role in the control of rotational kinematics while pursuing a moving target. This general-purpose steering function can guide animals toward desired spatial targets in any motivated behavior.

SummaryThe Ventral Tegmental Area (VTA) is a midbrain region implicated in a variety of motivated behaviors. However, the function of VTA GABAergic (Vgat+) neurons remains poorly understood. Here, using 3D motion capture, in vivo electrophysiology and calcium imaging, and optogenetics, we demonstrate a novel function of VTAVgat+ neurons. We found three distinct populations of neurons, each representing head angle about a principal axis of rotation: pitch, roll, and yaw. For each axis, opponent cell groups were found that increase firing when the head moves in one direction, and decrease firing in the opposite direction. Selective excitation and inhibition of VTAVgat+ neurons generate opposite rotational movements. The relationship between these neurons and head angle is degraded only at the time of reward consumption, at which point all head-angle related neuronal subpopulations show indistinguishable reward-related responses. Thus, VTAVgat+ neurons serve a critical role in the control of rotational kinematics while pursuing a moving target. This general-purpose steering function can guide animals toward desired spatial targets in any motivated behavior.

The ability to decipher where one needs to be and when it is most beneficial to be there are fundamental to the success of an organism. Humans along with other animals are able to extract duration and temporal order from external as well as internal stimuli, though lacking a dedicated sensory organ for time. A plethora of studies have focused on dorsal striatal and cerebellar networks as primary timing circuits with medium spiny neurons and Purkinje cells acting as the core temporal integrators within these circuits, respectively. However, recent findings have also made a strong case for the inclusion of the hippocampus with the discovery of hippocampal ‘time cells’. The denoted cells are pyramidal cells within the hippocampal CA1 area that exhibit increased firing rates in relation to elapsing durations, independent of the space and distance traveled. Previous behavioral work had implicated the role of the hippocampus in temporal processing, but only as of late has this work been substantiated with direct electrophysiological evidence. We describe the most recent evidence supporting the identification of ‘time cells’ in the subcortical structures of the striatum, hippocampus, and cerebellum and indicate how these different timing systems might be integrated into a common percept for time.

An integral component to the validity of timing models is their ability to accurately fit behavioral data from detection and discrimination tasks such as the temporal bisection procedure. Two of the most prominent timing models are the Sample Known Exactly (SKE), based on scalar timing theory, and the pseudo-logistic model (PLM). Recently, evidence accumulation models based on drift–diffusionprocesses (DDM) have been utilized for modeling temporal bisection data. Currently, there is no standard by which timing behavioral data are fit, resulting in the implementation of both theoretical and atheoretical models, such as generalized logistic functions (L4P). As differences in timing behavior have been shown across sub- and supra-second durations, a comparative evaluation of these 4 different types of models (SKE, PLM, L4P, and DDM) was conducted to assess each model’s ability to capture these differences using timing data from the temporal bisection procedure. Psychometric functions from rats, trained on a bisection task using sub-sec (200 ms vs. 800 ms.) and supra-sec (2 s vs. 8 s) conditions, were fit with each of the four models. Using Akaike Information Criterion (AIC) we demonstrate that theoretical models vastly outperformed the L4P across both duration ranges, Furthermore, significant differences existed in key parameters between L4P and PLM. Three DDM models were analyzed with varying degrees of freedom, which showed that allowing for non-decision time, drift rate, and starting point to vary across signal durations outperform simpler models ( Δ i ≥ 10) that only allowed for variation in drift rate or drift rate and starting point. These models explained variance in both choice and reaction time data. While we were unable to directly compare timing and temporal decision models the results from both demonstrate the need for a shift toward theoretically based models such as the SKE, PLM, or DDM which provide greater parsimony as well as provide for greater qualitative analysis and interpretation of the data.

The parafascicular nucleus (Pf) of the thalamus sends major projections to the basal ganglia, a group of subcortical nuclei involved in action initiation and selection. Here, we used optogenetics, 3D motion capture, in vivo electrophysiology, and viral-based neuroanatomical tracing to examine the contribution of the Pf to volitional movements in mice. We discovered that Pf neurons are highly correlated with movement velocity. Stimulation of glutamatergic (Vglut2+) neurons in the Pf generates turning and orienting movements. This effect was not due to Pf projections to the striatum, but to its projections to the subthalamic nucleus (STN), a major target of deep brain stimulation (DBS) for Parkinson9s disease (PD) patients. Moreover, selective excitation of either Pf Vglut2+ terminals in the STN or Pf cell bodies that send glutamatergic projections to the STN can restore natural movements in a bilateral mouse model of PD with complete akinesia. Our results reveal a novel thalamo-subthalamic pathway regulating movement initiation, and demonstrate a circuit mechanism that could explain the clinical efficacy of DBS for relief of PD motor symptoms.

We present an integrated view of interval timing and reinforcement learning (RL) in the brain. The computational goal of RL is to maximize future rewards, and this depends crucially on a representation of time. Different RL systems in the brain process time in distinct ways. A model-based system learns 'what happens when', employing this internal model to generate action plans, while a model-free system learns to predict reward directly from a set of temporal basis functions. We describe how these systems are subserved by a computational division of labor between several brain regions, with a focus on the basal ganglia and the hippocampus, as well as how these regions are influenced by the neuromodulator dopamine.