Thriving in neuroscience careers: Three lessons from 12+ years of the BRAINS Program.

The NINDS-funded BRAINS Program for neuroscientists from underrepresented and marginalized groups has positively impacted its participants and the field. We discuss three lessons to advance excellence and diversity: center relationships, provide ongoing engagement, and leverage programmatic expertise.

The medial prefrontal cortex during flexible decisions: Evidence for its role in distinct working memory processes.

During decisions that involve working memory, task-related information must be encoded, maintained across delays, and retrieved. Few studies have attempted to causally disambiguate how different brain structures contribute to each of these components of working memory. In the present study, we used transient optogenetic disruptions of rat medial prefrontal cortex (mPFC) during a serial spatial reversal learning (SSRL) task to test its role in these specific working memory processes. By analyzing numerous performance metrics, we found: (1) mPFC disruption impaired performance during only the choice epoch of initial discrimination learning of the SSRL task; (2) mPFC disruption impaired performance in dissociable ways across all task epochs (delay, choice, return) during flexible decision-making; (3) mPFC disruption resulted in a reduction of the typical vicarious-trial-and-error rate modulation that was related to changes in task demands. Taken together, these findings suggest that the mPFC plays an outsized role in working memory retrieval, becomes involved in encoding and maintenance when recent memories conflict with task demands, and enables animals to flexibly utilize working memory to update behavior as environments change.

Connecting Counterspaces and Community Cultural Wealth in a Professional Development Program.

This qualitative study analyzes the relationship between two concepts from critical race theory-counterspaces and community cultural wealth. Counterspaces are supportive, identity-affirming community spaces, while community cultural wealth highlights the importance of the knowledge, skills, and networks used by individuals belonging to marginalized groups to successfully navigate academia. This study investigates the hypothesis that the processes operating within counterspaces serve to strengthen an individual's access to their community cultural wealth. The study site is BRAINS, a U.S.-based professional development program for early-career academic neuroscientists from underrepresented groups. Findings revealed that two types of counterspace processes (narrative identity work and direct relational transactions) and three types of community cultural wealth (aspirational capital, social capital, and navigational capital) are most salient within BRAINS. After examining the complex interactions connecting counterspace processes and community cultural wealth, we offer recommendations for future professional development programs and research designed to broaden participation in academia.

Hippocampal beta rhythms as a bridge between sensory learning and memory-guided decision-making.

A pillar of systems neuroscience has been the study of neural oscillations. Research into these oscillations spans brain areas, species, and disciplines, giving us common ground for discussing typically disparate fields of neuroscience. In this review, we aim to strengthen the dialog between sensory systems research and learning and memory systems research by examining a 15-40 Hz oscillation known as the beta rhythm. Starting with foundational observations based largely in olfactory systems neuroscience, we review evidence suggesting beta-based activity may extend across sensory systems generally, as well as into the hippocampus and areas well known for coordinating decisions and memory-guided behaviors. After evaluating this work, we propose a framework wherein the hippocampal beta oscillation and its diverse coupling with other brain areas can support both sensory learning and memory-guided decision-making. Using this framework, we also propose circuitries that may support these processes, and experiments to test our hypothesis.

Response Flexibility: The Role of the Lateral Habenula.

The ability to make appropriate decisions that result in an optimal outcome is critical for survival. This process involves assessing the environment as well as integrating prior knowledge about the environment with information about one's current internal state. There are many neural structures that play critical roles in mediating these processes, but it is not yet known how such information coalesces to influence behavioral output. The lateral habenula (LHb) has often been cited as a structure critical for adaptive and flexible responding when environmental contexts and internal state changes. A challenge, however, has been understanding how LHb promotes response flexibility. In this review, we hypothesize that the LHb enables flexible responding following the integration of context memory and internal state information by signaling downstream brainstem structures known to drive hippocampal theta. In this way, animals respond more flexibly in a task situation not because the LHb selects a particular action, but rather because LHb enhances a hippocampal neural state that is often associated with greater attention, arousal, and exploration. In freely navigating animals, these are essential conditions that are needed to discover and implement appropriate alternative choices and behaviors. As a corollary to our hypothesis, we describe short- and intermediate-term functions of the LHb. Finally, we discuss the effects on the behavior of LHb dysfunction in short- and intermediate-timescales, and then suggest that new therapies may act on the LHb to alleviate the behavioral impairments following long-term LHb disruption.

Lateral Habenula Beyond Avoidance: Roles in Stress, Memory, and Decision-Making With Implications for Psychiatric Disorders.

In this Perspective review, we highlight some of the less explored aspects of lateral habenula (LHb) function in contextual memory, sleep, and behavioral flexibility. We provide evidence that LHb is well-situated to integrate different internal state and multimodal sensory information from memory-, stress-, motivational-, and reward-related circuits essential for both survival and decision making. We further discuss the impact of early life stress (ELS) on LHb function as an example of stress-induced hyperactivity and dysregulation of neuromodulatory systems within the LHb that promote anhedonia and motivational deficits following ELS. We acknowledge that recent technological advancements in manipulation and recording of neural circuits in simplified and well-controlled behavioral paradigms have been invaluable in our understanding of the critical role of LHb in motivation and emotional regulation as well as the involvement of LHb dysfunction in stress-induced psychopathology. However, we also argue that the use of ethologically-relevant behaviors with consideration of complex aspects of decision-making is warranted for future studies of LHb contributions in a wide range of psychiatric illnesses. We conclude this Perspective with some of the outstanding issues for the field to consider where a multi-systems approach is needed to investigate the complex nature of LHb circuitry interactions with environmental stimuli that predisposes psychiatric disorders.

A Machine Learning Approach for Detecting Vicarious Trial and Error Behaviors.

Vicarious trial and error behaviors (VTEs) indicate periods of indecision during decision-making, and have been proposed as a behavioral marker of deliberation. In order to understand the neural underpinnings of these putative bridges between behavior and neural dynamics, researchers need the ability to readily distinguish VTEs from non-VTEs. Here we utilize a small set of trajectory-based features and standard machine learning classifiers to identify VTEs from non-VTEs for rats performing a spatial delayed alternation task (SDA) on an elevated plus maze. We also show that previously reported features of the hippocampal field potential oscillation can be used in the same types of classifiers to separate VTEs from non-VTEs with above chance performance. However, we caution that the modest classifier success using hippocampal population dynamics does not identify many trials where VTEs occur, and show that combining oscillation-based features with trajectory-based features does not improve classifier performance compared to trajectory-based features alone. Overall, we propose a standard set of features useful for trajectory-based VTE classification in binary decision tasks, and support previous suggestions that VTEs are supported by a network including, but likely extending beyond, the hippocampus.

A selective role for the mPFC during choice and deliberation, but not spatial memory retention over short delays.

Important interactions between memory and decision-making processes are required to maintain high-levels of spatial working memory task performance. Past research reveals that the medial prefrontal cortex (mPFC) and hippocampus (HPC) are both vital structures involved in these processes. Recent evidence suggests that interactions between these two structures are dynamic and task dependent. However, there exists uncertainty surrounding the specific conditions that recruit mPFC contributions to these tasks, specifically regarding its role in retaining information online during delay periods. To address this issue, we tested rats on a spatial-delayed alternation task in which we utilized a closed-loop optogenetic system to transiently disrupt mPFC activity during different task epochs (delay, choice, return). By analyzing the effects of mPFC disruption on choice accuracy and a deliberative behavior known as vicarious-trial-and-error (VTE), our study revealed several interesting findings regarding the role of the mPFC in spatial-working memory tasks. The main findings include: (a) choice accuracy in the spatial-delayed alternation (SDA) task was impaired when the mPFC was disrupted during the choice epoch and not delay or return epochs, (b) mPFC disruption resulted in a non-epoch specific reduction in VTE occurrence which correlated with impairments in task performance. Taken together, findings from this study suggest that, during spatial decision-making, contributions made by the mPFC are specific to points of deliberation and choice (not delay), and that VTEs are a deliberative behavior which relies on intact mPFC function.

Loss of Sensitivity to Rewards by Dopamine Neurons May Underlie Age-Related Increased Probability Discounting.

Normative aging is known to affect how decisions are made in risky situations. Although important individual variability exists, on average, aging is accompanied by greater risk aversion. Here the behavioral and neural mechanisms of greater risk aversion were examined in young and old rats trained on an instrumental probability discounting task. Consistent with the literature, old rats showed greater discounting of reward value when the probability of obtaining rewards dropped below 100%. Behaviorally, reward magnitude discrimination was the same between young and old rats, and yet these same rats exhibited reduced sensitivity to positive, but not negative, choice outcomes. The latter behavioral result was congruent with additional findings that the aged ventral tegmental neurons (including dopamine cells) were less responsive to rewards when compared to the same cell types recorded from young animals. In sum, it appears that reduced responses of dopamine neurons to rewards contribute to aging-related changes in risky decisions.

Selective Functional Interaction Between the Lateral Habenula and Hippocampus During Different Tests of Response Flexibility.

The lateral habenula (LHb) has been shown to play critical roles in a variety of appetitive tasks (e.g., spatial memory and object recognition) that require animals to flexibly respond to changing task conditions. These types of tasks are known to be dependent on hippocampus (HPC) and/or medial prefrontal cortex (mPFC), suggesting that the LHb contributes to the limbic memory circuit. Here we provide new evidence that the LHb and HPC play distinct but complimentary roles in tasks that require flexible responding to changing task conditions. Experiment 1 tested whether the LHb is needed for the performance of a HPC-dependent maze-based spatial delayed alternation task. The importance of interactions between the LHb and HPC to accomplish the same spatial delayed alternation task was tested in Experiment 2 where the LHb and HPC were disconnected both ipsilaterally and contralaterally. Experiment 3 tested LHb's involvement in a standard behavioral economic task that requires flexible responding (maze-based delayed discounting), a task previously shown to rely on HPC. Results of Experiment 1, revealed that LHb inactivation impairs spatial delayed alternation during asymptotic performance but not during initial learning. Importantly, working memory did not appear to be affected as performance remained above chance levels both during initial learning and asymptotic testing. Experiment 2 showed that ipsilateral and contralateral disconnection of the LHb and HPC led to impaired performance on the spatial delayed alternation task. Impairments were not observed after unilateral inactivation of only one structure. Results of Experiment 3 were similar to our previous report of the effects of HPC inactivation: LHb inactivation impaired delayed discounting. All effects could not be accounted for by changes in reward magnitude discrimination, reward location per se, or sex of the animal. These findings, combined with other recent publications confirms and extends our working hypothesis that the LHb enables adaptive and flexible responding, particularly when established rules must be flexibly applied on a trial by trial basis. Since there are no known direct anatomical connections between LHb and HPC, future research is needed to understand how these structures communicate to enable flexible and rapid responding.

Transient Input-Specific Neural Plasticity in the Lateral Habenula Facilitates Learning.

In this issue of Neuron, Trusel et al. (2019) demonstrate that circuit-specific plasticity in the lateral habenula is dynamically involved in translating CS-US contingencies into cue-driven avoidance behavior. Disruption of this plasticity prevents learning about CS-US relationships when they are uncertain.

A Novel Role for the Periaqueductal Gray in Consummatory Behavior.

The periaqueductal gray (PAG) has a well-established role in pain processing, autonomic function and behavioral responses to fear. Anatomical work suggests the PAG may mediate food intake and reward processing as it has extensive reciprocal connections within brain circuits that mediate appetitive processes and consummatory behaviors such as prefrontal cortex, hypothalamus, amygdala, parabrachial nucleus (PBN) and ventral tegmental area (Kelley et al., 2005). Therefore, we investigated if the PAG of hungry rats has a functional role in appetitive and consummatory behaviors. To address this, PAG was pharmacologically inactivated during a spatial working memory task with muscimol (0.1-0.3 µg), a GABAA agonist via intracranial infusion. Inactivation of PAG led to reduced intake of food rewards and increased errors on this task. To focus on the specific effects PAG inactivation had on food consumption, PAG was inactivated during two separate food intake tasks in a separate group of rats. Again, PAG inactivation resulted in a significant decrease in food consumption, as well as an increased latency to consume food. We next investigated PAG neural responses to reward encounters. A different group of rats performed the same task used in Experiment 1 while the in vivo activity of PAG neurons was recorded. In a subset of PAG neurons, reward encounters elicited phasic excitation. A separate subset of PAG neurons were inhibited during reward encounters. These responses scaled with the size of the reward, with sustained excitation or inhibition in response to large rewards compared to small. Our data also show that separate groups of PAG neurons in awake behaving animals display either increased and decreased neural responses to reward encounters. Additionally, a proportion of neurons were modulated by the animals' velocity. This study is the first to show that PAG neurons process reward-related information, perhaps to mediate consummatory behaviors related to food consumption.

Dynamic coding of predatory information between the prelimbic cortex and lateral amygdala in foraging rats.

Predation is considered a major selective pressure in the evolution of fear, but the neurophysiology of predator-induced fear is unknown. We simultaneously recorded lateral amygdala (LA) and prelimbic (PL) area neuronal activities as rats exited a safe nest to search for food in an open space before, during, and after encountering a "predator" robot programmed to surge from afar. Distinct populations of LA neurons transiently increased spiking as rats either advanced or fled the robot, whereas PL neurons showed longer-lasting spike trains that preceded and persisted beyond LA activity. Moreover, discrete LA-PL cell pairs displayed correlated firings only when the animals either approached or fled the robot. These results suggest a general fear function of the LA-PL circuit where the PL participates in the initial detection of potential threats, the LA signals the occurrence of real threats, and the dynamic LA-PL interaction optimizes defensive readiness for action.

Control of behavioral flexibility by the lateral habenula.

The ability to rapidly switch behaviors in dynamic environments is fundamental to survival across species. Recognizing when an ongoing behavioral strategy should be replaced by an alternative one requires the integration of a diverse number of cues both internal and external to the organism including hunger, stress, or the presence of reward predictive cues. Increasingly sophisticated behavioral paradigms coupled with state of the art electrophysiological and pharmacological approaches have delineated a brain circuit involved in behavioral flexibility. However, how diverse contextual cues are integrated to influence strategy selection on a trial by trial basis remains largely unknown. One promising candidate for integration of internal and external cues to determine whether an ongoing behavioral strategy is appropriate is the lateral habenula (LHb). The LHb receives input from many brain areas that signal both internal and external environmental contexts and in turn projects to areas involved in behavioral monitoring and plasticity. This review examines how these connections, combined with recent pharmacological and electrophysiological results reveal a critical role for the LHb in behavioral flexibility in dynamic environments. This proposed role extends the known contributions of the LHb to motivated behaviors and suggests that the fundamental role of the LHb in these behaviors goes beyond signaling rewards and punishments to dopaminergic systems.

The Lateral Habenula and Adaptive Behaviors.

The evolutionarily conserved lateral habenula (LHb) enables dynamic responses to continually changing contexts and environmental conditions. A model is proposed to account for greater mnemonic and contextual control over LHb-mediated response flexibility as vertebrate brains became more complex. The medial prefrontal cortex (mPFC) provides instructions for context-specific responses to LHb, which assesses the extent to which this response information matches the motivation or internal state of the individual. LHb output either maintains a prior response (match) or leads to alternative responses (mismatch). It may also maintain current spatial and temporal processing in hippocampus (match), or alter such activity to reflect updated trajectory and sequenced information (mismatch). A response flexibility function of the LHb is consistent with poor behavioral control following its disruption (e.g., in depression).

The BRAINS Program: Transforming Career Development to Advance Diversity and Equity in Neuroscience.

In order to better prepare trainees and advance diversity in neuroscience, career development must move beyond scientific skills. The BRAINS Program's continuous professional development model positively impacts participants' careers by fostering a sense of community and creating a counterspace for critical conversations.

Hippocampal neural activity reflects the economy of choices during goal-directed navigation.

Distinguishing spatial contexts is likely essential for the well-known role of the hippocampus in episodic memory. We studied whether types of hippocampal neural organization thought to underlie context discrimination are impacted by learned economic considerations of choice behavior. Hippocampal place cells and theta activity were recorded as rats performed a maze-based probability discounting task that involved choosing between a small certain reward or a large probabilistic reward. Different spatial distributions of place fields were observed in response to changes in probability, the outcome of the rats' choice, and whether or not rats were free to make that choice. The degree to which the reward location was represented by place cells scaled with the expected probability of rewards. Theta power increased around the goal location also in proportion to the expected probability of signaled rewards. Furthermore, theta power dynamically varied as specific econometric information was obtained "on the fly" during task performance. Such an economic perspective of memory processing by hippocampal place cells expands our view of the nature of context memories retrieved by hippocampus during adaptive navigation.

A framework for understanding and advancing intertemporal choice research using rodent models.

Intertemporal choices are common and consequential to private and public life. Thus, there is considerable interest in understanding the neural basis of intertemporal decision making. In this minireview, we briefly describe conceptual and psychological perspectives on intertemporal choice and then provide a comprehensive evaluation of the neural structures and signals that comprise the underlying cortico-limbic-striatal circuit. Even though great advances have been made, our understanding of the neurobiology of intertemporal choice is still in its infancy because of the complex and dynamic nature of this form of decision making. We close by briefly discussing recommendations for the future study of intertemporal choice research.

The Lateral Habenula Circuitry: Reward Processing and Cognitive Control.

There has been a growing interest in understanding the role of the lateral habenula (LHb) in reward processing, affect regulation, and goal-directed behaviors. The LHb gets major inputs from the habenula-projecting globus pallidus and the mPFC, sending its efferents to the dopaminergic VTA and SNc, serotonergic dorsal raphe nuclei, and the GABAergic rostromedial tegmental nucleus. Recent studies have made advances in our understanding of the LHb circuit organization, yet the precise mechanisms of its involvement in complex behaviors are largely unknown. To begin to address this unresolved question, we present here emerging cross-species perspectives with a goal to provide a more refined understanding of the role of the LHb circuits in reward and cognition. We begin by highlighting recent findings from rodent experiments using optogenetics, electrophysiology, molecular, pharmacology, and tracing techniques that reveal diverse neural phenotypes in the LHb circuits that may underlie previously undescribed behavioral functions. We then discuss results from electrophysiological studies in macaques that suggest that the LHb cooperates with the anterior cingulate cortex to monitor action outcomes and signal behavioral adjustment. Finally, we provide an integrated summary of cross-species findings and discuss how further research on the connectivity, neural signaling, and physiology of the LHb circuits can deepen our understanding of the role of the LHb in normal and maladaptive behaviors associated with mental illnesses and drug abuse.