Precise 3D Localization of Intracerebral Implants with a simple Brain Clearing Method.

Determining the localization of intracerebral implants in rodent brain stands as a critical final step in most physiological and behaviroral studies, especially when targeting deep brain nuclei. Conventional histological approaches, reliant on manual estimation through sectioning and slice examination, are error-prone, potentially complicating data interpretation. Leveraging recent advances in tissue-clearing techniques and light-sheet fluorescence microscopy, we introduce a method enabling virtual brain slicing in any orientation, offering precise implant localization without the limitations of traditional tissue sectioning. To illustrate the method's utility, we present findings from the implantation of linear silicon probes into the midbrain interpeduncular nucleus (IPN) of anesthetized transgenic mice expressing chanelrhodopsin-2 and enhanced yellow fluorescent protein under the choline acetyltransferase (ChAT) promoter/enhancer regions (ChAT-Chr2-EYFP mice). Utilizing a fluorescent dye applied to the electrode surface, we visualized both the targeted area and the precise localization, enabling enhanced inter-subject comparisons. Three dimensional (3D) brain renderings, presented effortlessly in video format across various orientations, showcase the versatility of this approach.

Thalamic input to motor cortex facilitates goal-directed action initiation.

Prompt execution of planned motor action is essential for survival. The interactions between frontal cortical circuits and the basal ganglia are central to goal-oriented action selection and initiation.1-4 In rodents, the ventromedial thalamic nucleus (VM) is one of the critical nodes that conveys the output of the basal ganglia to the frontal cortical areas including the anterior lateral motor cortex (ALM).5-9 Recent studies showed the critical role of ALM and its interplay with the motor thalamus in preparing sensory-cued rewarded movements, specifically licking.10-12 Work in primates suggests that the basal ganglia output to the motor thalamus transmits an urgency or vigor signal,13-15 which leads to shortened reaction times and faster movement initiation. As yet, little is known about what signals are transmitted from the motor thalamus to the cortex during cued movements and how these signals contribute to movement initiation. In the present study, we employed a tactile-cued licking task in mice while monitoring reaction times of the initial lick. We found that inactivation of ALM delayed the initiation of cued licking. Two-photon Ca2+ imaging of VM axons revealed that the majority of the axon terminals in ALM were transiently active during licking. Their activity was predictive of the time of the first lick. Chemogenetic and optogenetic manipulation of VM axons in ALM indicated that VM inputs facilitate the initiation of cue-triggered and impulsive licking in trained mice. Our results suggest that VM thalamocortical inputs increase the probability and vigor of initiating planned motor responses.

Premotor Ramping of Thalamic Neuronal Activity Is Modulated by Nigral Inputs and Contributes to Control the Timing of Action Release.

The ventromedial (VM)/ventro-anterior-lateral (VAL) motor thalamus is a key junction within the brain circuits sustaining normal and pathologic motor control functions and decision-making. In this area of thalamus, on one hand, the inhibitory nigro-thalamic pathway provides a main output from the basal ganglia, and, on the other hand, motor thalamo-cortical loops are involved in the maintenance of ramping preparatory activity before goal-directed movements. To better understand the nigral impact on thalamic activity, we recorded electrophysiological responses from VM/VAL neurons while male and female mice were performing a delayed right/left decision licking task. Analysis of correct (corr) and error trials revealed that thalamic ramping activity was stronger for premature licks (impulsive action) and weaker for trials with no licks [omission (omi)] compared with correct trials. Suppressing ramping activity through optogenetic activation of nigral terminals in the motor thalamus during the delay epoch of the task led to a reduced probability of impulsive action and an increased amount of omissions trials. We propose a parsimonious model explaining our data and conclude that a thalamic ramping mechanism contributes to the control of proper timing of action release and that inhibitory nigral inputs are sufficient to interrupt this mechanism and modulate the amount of motor impulsivity in this task.SIGNIFICANCE STATEMENT Coordinated neural activity in motor circuits is essential for correct movement preparation and execution, and even slight imbalances in neural processing can lead to failure in behavioral tasks or motor disorders. Here we focused on how failure to regulate the control of activity balance in the motor thalamus can be implicated in impulsive action release or omissions to act, through an activity ramping mechanism that is required for proper action release. Using optogenetic activation of inhibitory basal ganglia terminals in motor thalamus we show that basal ganglia input is well positioned to control this ramping activity and determine the timing of action initiation.

Low- and high-gamma oscillations deviate in opposite directions from zero-phase synchrony in the limbic corticostriatal loop.

The loop structure of cortico-striatal anatomy in principle enables both descending (cortico-striatal) and ascending (striato-cortical) influences, but the factors that regulate the flow of information in these loops are not known. We report that low- and high-gamma oscillations (∼50 and ∼80 Hz, respectively) in the local field potential of freely moving rats are highly synchronous between the infralimbic region of the medial prefrontal cortex (mPFC) and the ventral striatum (vStr). Strikingly, high-gamma oscillations in mPFC preceded those in vStr, whereas low-gamma oscillations in mPFC lagged those in vStr, with short (∼1 ms) time lags. These systematic deviations from zero-phase synchrony were consistent across measures based on amplitude cross-correlation and phase slopes and were robustly maintained between behavioral states and different individual subjects. Furthermore, low- and high-gamma oscillations were associated with distinct ensemble spiking patterns in vStr, even when controlling for overt behavioral differences and slow changes in neural activity. These results imply that neural activity in vStr and mPFC is tightly coupled at the gamma timescale and raise the intriguing possibility that frequency-specific deviations from this coupling may signal transient leader-follower switches.

Retrospectively and prospectively modulated hippocampal place responses are differentially distributed along a common path in a continuous T-maze.

Hippocampal place responses can be prospectively or retrospectively modulated by the animal's future or prior trajectory. Two main hypotheses explain this. The "multiple-map hypothesis" switches between different maps for different trajectories (rate remapping). In contrast, in the "buffer hypothesis," the hippocampus encodes an ongoing representation that includes the recent past and/or the impending future choice. This study examines the distribution of prospective and retrospective responses distributed along a common path in a continuous T-maze (providing all four combinations of provenance and destination) during a visual discrimination task. The multiple-map hypothesis predicts either uniform distributions or concerted shifts about a task-decision relevant point, whereas the buffer hypothesis predicts a time-limited overexpression around choice points (with retrospective responses after the central arm entry point and prospective responses nearer its exit). Here bilateral recordings in the dorsal CA1 region of the rat hippocampus show that retrospective responses were twice as prevalent as prospective responses. Furthermore, retrospective and prospective modulations have distinct spatial distributions, with retrospective primarily in the first two-thirds of the central arm and prospective restricted to the last third. To test for possible trial-by-trial remapping in relation to the two-thirds transition point, data from the first and second halves of the sessions were compared. Backward drift of path-modulated activity was significant only for retrospective, but not prospective, fields. Thus, these data are more consistent with the buffer hypothesis. Retrospective and prospective modulation would then participate in a single hippocampal representation of spatial and behavioral context.

A network state linking motivation and action in the nucleus accumbens.

In this issue of Neuron, McGinty et al. (2013) report that the activity of cue-responsive neurons in the rat nucleus accumbens predicts the vigor of the subsequent approach movement. The characterization of this network state between motivation and action lends novel mechanistic insight to a spectrum of cue-elicited behaviors.

Dynamics of decision-related activity in hippocampus.

Place-selective activity in hippocampal neurons can be modulated by the trajectory that will be taken in the immediate future ("prospective coding"), information that could be useful in neural processes elaborating choices in route planning. To determine if and how hippocampal prospective neurons participate in decision making, we measured the time course of the evolution of prospective activity by recording place responses in rats performing a T-maze alternation task. After five or seven alternation trials, the routine was unpredictably interrupted by a photodetector-triggered visual cue as the rat crossed the middle of central arm, signaling it to suddenly change its intended choice. Comparison of the delays between light cue presentation and the onset of prospective activity for neurons with firing fields at various locations after the trigger point revealed a 420 ms processing delay. This surprisingly long delay indicates that prospective activity in the hippocampus appears much too late to generate planning or decision signals. This provides yet another example of a prominent brain activity that is unlikely to play a functional role in the cognitive function that it appears to represent (planning future trajectories). Nonetheless, the hippocampus may provide other contextual information to areas active at the earliest stages of selecting future paths, which would then return signals that help establish hippocampal prospective activity.