Where Actions Meet Outcomes: Medial Prefrontal Cortex, Central Thalamus, and the Basal Ganglia.

Medial prefrontal cortex (mPFC) interacts with distributed networks that give rise to goal-directed behavior through afferent and efferent connections with multiple thalamic nuclei and recurrent basal ganglia-thalamocortical circuits. Recent studies have revealed individual roles for different thalamic nuclei: mediodorsal (MD) regulation of signaling properties in mPFC neurons, intralaminar control of cortico-basal ganglia networks, ventral medial facilitation of integrative motor function, and hippocampal functions supported by ventral midline and anterior nuclei. Large scale mapping studies have identified functionally distinct cortico-basal ganglia-thalamocortical subnetworks that provide a structural basis for understanding information processing and functional heterogeneity within the basal ganglia. Behavioral analyses comparing functional deficits produced by lesions or inactivation of specific thalamic nuclei or subregions of mPFC or the basal ganglia have elucidated the interdependent roles of these areas in adaptive goal-directed behavior. Electrophysiological recordings of mPFC neurons in rats performing delayed non-matching-to position (DNMTP) and other complex decision making tasks have revealed populations of neurons with activity related to actions and outcomes that underlie these behaviors. These include responses related to motor preparation, instrumental actions, movement, anticipation and delivery of action outcomes, memory delay, and spatial context. Comparison of results for mPFC, MD, and ventral pallidum (VP) suggest critical roles for mPFC in prospective processes that precede actions, MD for reinforcing task-relevant responses in mPFC, and VP for providing feedback about action outcomes. Synthesis of electrophysiological and behavioral results indicates that different networks connecting mPFC with thalamus and the basal ganglia are organized to support distinct functions that allow organisms to act efficiently to obtain intended outcomes.

Chronic, Multi-Site Recordings Supported by Two Low-Cost, Stationary Probe Designs Optimized to Capture Either Single Unit or Local Field Potential Activity in Behaving Rats.

Rodent models of cognitive behavior have greatly contributed to our understanding of human neuropsychiatric disorders. However, to elucidate the neurobiological underpinnings of such disorders or impairments, animal models are more useful when paired with methods for measuring brain function in awake, behaving animals. Standard tools used for systems-neuroscience level investigations are not optimized for large-scale and high-throughput behavioral battery testing due to various factors including cost, time, poor longevity, and selective targeting limited to measuring only a few brain regions at a time. Here we describe two different "user-friendly" methods for building extracellular electrophysiological probes that can be used to measure either single units or local field potentials in rats performing cognitive tasks. Both probe designs leverage several readily available, yet affordable, commercial products to facilitate ease of production and offer maximum flexibility in terms of brain-target locations that can be scalable (32-64 channels) based on experimental needs. Our approach allows neural activity to be recorded simultaneously with behavior and compared between micro (single unit) and more macro (local field potentials) levels of brain activity in order to gain a better understanding of how local brain regions and their connected networks support cognitive functions in rats. We believe our novel probe designs make collecting electrophysiology data easier and will begin to fill the gap in knowledge between basic and clinical research.

Electrophysiological Correlates of Rodent Default-Mode Network Suppression Revealed by Large-Scale Local Field Potential Recordings.

The default-mode network (DMN) in humans consists of a set of brain regions that, as measured with functional magnetic resonance imaging (fMRI), show both intrinsic correlations with each other and suppression during externally oriented tasks. Resting-state fMRI studies have previously identified similar patterns of intrinsic correlations in overlapping brain regions in rodents (A29C/posterior cingulate cortex, parietal cortex, and medial temporal lobe structures). However, due to challenges with performing rodent behavior in an MRI machine, it is still unclear whether activity in rodent DMN regions are suppressed during externally oriented visual tasks. Using distributed local field potential measurements in rats, we have discovered that activity in DMN brain regions noted above show task-related suppression during an externally oriented visual task at alpha and low beta-frequencies. Interestingly, this suppression (particularly in posterior cingulate cortex) was linked with improved performance on the task. Using electroencephalography recordings from a similar task in humans, we identified a similar suppression of activity in posterior cingulate cortex at alpha/low beta-frequencies. Thus, we have identified a common electrophysiological marker of DMN suppression in both rodents and humans. This observation paves the way for future studies using rodents to probe circuit-level functioning of DMN function. SIGNIFICANCE: Here we show that alpha/beta frequency oscillations in rats show key features of DMN activity, including intrinsic correlations between DMN brain regions, task-related suppression, and interference with attention/decision-making. We found similar task-related suppression at alpha/low beta-frequencies of DMN activity in humans.

Central Thalamic-Medial Prefrontal Control of Adaptive Responding in the Rat: Many Players in the Chamber.

The medial prefrontal cortex (mPFC) has robust afferent and efferent connections with multiple nuclei clustered in the central thalamus. These nuclei are elements in large-scale networks linking mPFC with the hippocampus, basal ganglia, amygdala, other cortical areas, and visceral and arousal systems in the brainstem that give rise to adaptive goal-directed behavior. Lesions of the mediodorsal nucleus (MD), the main source of thalamic input to middle layers of PFC, have limited effects on delayed conditional discriminations, like DMTP and DNMTP, that depend on mPFC. Recent evidence suggests that MD sustains and amplifies neuronal responses in mPFC that represent salient task-related information and is important for detecting and encoding contingencies between actions and their consequences. Lesions of rostral intralaminar (rIL) and ventromedial (VM) nuclei produce delay-independent impairments of egocentric DMTP and DNMTP that resemble effects of mPFC lesions on response speed and accuracy: results consistent with projections of rIL to striatum and VM to motor cortices. The ventral midline and anterior thalamic nuclei affect allocentric spatial cognition and memory consistent with their connections to mPFC and hippocampus. The dorsal midline nuclei spare DMTP and DNMTP. They have been implicated in behavioral-state control and response to salient stimuli in associative learning. mPFC functions are served during DNMTP by discrete populations of neurons with responses related to motor preparation, movements, lever press responses, reinforcement anticipation, reinforcement delivery, and memory delay. Population analyses show that different responses are timed so that they effectively tile the temporal interval from when DNMTP trials are initiated until the end. Event-related responses of MD neurons during DNMTP are predominantly related to movement and reinforcement, information important for DNMTP choice. These responses closely mirror the activity of mPFC neurons with similar responses. Pharmacological inactivation of MD and adjacent rIL affects the expression of diverse action- and outcome-related responses of mPFC neurons. Lesions of MD before training are associated with a shift away from movement-related responses in mPFC important for DNMTP choice. These results suggest that MD has short-term effects on the expression of event-related activity in mPFC and long-term effects that tune mPFC neurons to respond to task-specific information.

Effects of choice on neuronal activity in anterior cingulate, prelimbic, and infralimbic cortices in the rat: Comparison of serial lever pressing with delayed nonmatching to position.

The ability to choose between response alternatives based on their likely consequences depends on distributed neural circuits that involve rodent medial prefrontal cortex (mPFC). To understand the effects of choice on mPFC function, we compared the activity of mPFC neurons in rats performing two tasks: dynamic delayed nonmatching to position (dDNMTP), a task with a prefrontal-dependent conditional choice, and serial lever pressing (SLP), a task lacking a choice but trained in the same apparatus with sequences of actions and reinforcements matched to dDNMTP. More neurons exhibited event-related responses during dDNMTP than SLP. Average firing rate during recording sessions was higher during dDNMTP for neurons with event-related responses, but lower for neurons with activity unrelated to behavioural events. Thus, compared to SLP, dDNMTP appears to enhance the activity of neurons that represent behaviourally relevant information and to suppress the activity of neurons that do not. dDNMTP was associated with responses related to preparation and memory delay that were not observed during SLP as well as enhanced responses related to movement and reinforcement. These results provide evidence that choice in the dDNMTP task is associated with adaptive changes in background firing rates and coding properties of mPFC neurons.

Central thalamic inactivation impairs the expression of action- and outcome-related responses of medial prefrontal cortex neurons in the rat.

The mediodorsal (MD) and adjacent intralaminar (IL) and midline nuclei provide the main thalamic input to the medial prefrontal cortex (mPFC) and are critical for associative learning and decision-making. MD neurons exhibit activity related to actions and outcomes that mirror responses of mPFC neurons in rats during dynamic delayed non-match to position (dDNMTP), a variation of DNMTP where start location is varied randomly within an open octagonal arena to avoid confounding behavioral events with spatial location. To test whether the thalamus affects the expression of these responses in mPFC, we inhibited the central thalamus unilaterally by microinjecting muscimol at doses and sites found to affect decision-making when applied bilaterally. Unilateral inactivation reduced normalized task-related responses in the ipsilateral mPFC without disrupting behavior needed to characterize event-related neuronal activity. Our results extend earlier findings that focused on delay-related activity by showing that central thalamic inactivation interferes with responses related to actions and outcomes that occur outside the period of memory delay. These findings are consistent with the broad effects of central thalamic lesions on behavioral measures of reinforcement-guided responding. Most (7/8) of the prefrontal response types affected by thalamic inactivation have also been observed in MD during dDNMTP. These results support the hypothesis that MD and IL act as transthalamic gates: monitoring prefrontal activity through corticothalamic inputs; integrating this information with signals from motivational and sensorimotor systems that converge in thalamus; and acting through thalamocortical projections to enhance expression of neuronal responses in the PFC that support adaptive goal-directed behavior.

Representation of actions and outcomes in medial prefrontal cortex during delayed conditional decision-making: Population analyses of single neuron activity.

BACKGROUND: To respond adaptively in a dynamic environment, it is important for organisms to utilise information about recent events to decide between response options. METHODS: To examine the role of medial prefrontal cortex in adaptive decision-making, we recorded single neuron activity in rats performing a dynamic delayed non-matching to position task. RESULTS: We recorded activity from 1335 isolated neurons, 458 (34%) with criterion event-related activity, of which 431 (94%) exhibited 1 of 10 distinct excitatory response types: five at different times relative to delivery (or lack) of reinforcement following sample and choice responses and five correlated with movements or lever press actions that occurred multiple times in each trial. Normalised population averages revealed a precisely timed cascade of population responses representing the temporal organisation behavioural events that constitute delayed non-matching to position trials. Firing field analyses identified a subset of neurons with restricted spatial fields: responding to the conjunction of a behavioural event with a specific location. Anatomical analyses showed considerable overlap in the distribution of different response types in medial prefrontal cortex with a significant trend for dorsal areas to contain more neurons with action-related activity and ventral areas more responses related to action outcomes. CONCLUSION: These results indicate that medial prefrontal cortex contains discrete populations of neurons that represent the temporal organisation of actions and outcomes during delayed non-matching to position trials. They support the hypothesis that medial prefrontal cortex promotes flexible control of complex behaviours by action-outcome contingencies.

Mediodorsal Thalamic Neurons Mirror the Activity of Medial Prefrontal Neurons Responding to Movement and Reinforcement during a Dynamic DNMTP Task.

The mediodorsal nucleus (MD) interacts with medial prefrontal cortex (mPFC) to support learning and adaptive decision-making. MD receives driver (layer 5) and modulatory (layer 6) projections from PFC and is the main source of driver thalamic projections to middle cortical layers of PFC. Little is known about the activity of MD neurons and their influence on PFC during decision-making. We recorded MD neurons in rats performing a dynamic delayed nonmatching to position (dDNMTP) task and compared results to a previous study of mPFC with the same task (Onos et al., 2016). Criterion event-related responses were observed for 22% (254/1179) of neurons recorded in MD, 237 (93%) of which exhibited activity consistent with mPFC response types. More MD than mPFC neurons exhibited responses related to movement (45% vs. 29%) and reinforcement (51% vs. 27%). MD had few responses related to lever presses, and none related to preparation or memory delay, which constituted 43% of event-related activity in mPFC. Comparison of averaged normalized population activity and population response times confirmed the broad similarity of common response types in MD and mPFC and revealed differences in the onset and offset of some response types. Our results show that MD represents information about actions and outcomes essential for decision-making during dDNMTP, consistent with evidence from lesion studies that MD supports reward-based learning and action-selection. These findings support the hypothesis that MD reinforces task-relevant neural activity in PFC that gives rise to adaptive behavior.

Prefrontal Neurons Encode Actions and Outcomes in Conjunction with Spatial Location in Rats Performing a Dynamic Delayed Non-Match to Position Task.

To respond adaptively to change organisms must utilize information about recent events and environmental context to select actions that are likely to produce favorable outcomes. We developed a dynamic delayed nonmatching to position task to study the influence of spatial context on event-related activity of medial prefrontal cortex neurons during reinforcement-guided decision-making. We found neurons with responses related to preparation, movement, lever press responses, reinforcement, and memory delays. Combined event-related and video tracking analyses revealed variability in spatial tuning of neurons with similar event-related activity. While all correlated neurons exhibited spatial tuning broadly consistent with relevant task events, for instance reinforcement-related activity concentrated in locations where reinforcement was delivered, some had elevated activity in more specific locations, for instance reinforcement-related activity in one of several locations where reinforcement was delivered. Timing analyses revealed a limited set of distinct response types with activity time-locked to critical behavioral events that represent the temporal organization of dDNMTP trials. Our results suggest that reinforcement-guided decision-making emerges from discrete populations of medial prefrontal neurons that encode information related to planned or ongoing movements and actions and anticipated or actual action-outcomes in conjunction with information about spatial context.

The neurobiology of thalamic amnesia: Contributions of medial thalamus and prefrontal cortex to delayed conditional discrimination.

Although medial thalamus is well established as a site of pathology associated with global amnesia, there is uncertainty about which structures are critical and how they affect memory function. Evidence from human and animal research suggests that damage to the mammillothalamic tract and the anterior, mediodorsal (MD), midline (M), and intralaminar (IL) nuclei contribute to different signs of thalamic amnesia. Here we focus on MD and the adjacent M and IL nuclei, structures identified in animal studies as critical nodes in prefrontal cortex (PFC)-related pathways that are necessary for delayed conditional discrimination. Recordings of PFC neurons in rats performing a dynamic delayed non-matching-to position (DNMTP) task revealed discrete populations encoding information related to planning, execution, and outcome of DNMTP-related actions and delay-related activity signaling previous reinforcement. Parallel studies recording the activity of MD and IL neurons and examining the effects of unilateral thalamic inactivation on the responses of PFC neurons demonstrated a close coupling of central thalamic and PFC neurons responding to diverse aspects of DNMTP and provide evidence that thalamus interacts with PFC neurons to give rise to complex goal-directed behavior exemplified by the DNMTP task.