Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia.

The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct and indirect pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions.

Goal-directed learning in adolescence: neurocognitive development and contextual influences.

Adolescence is a time during which we transition to independence, explore new activities and begin pursuit of major life goals. Goal-directed learning, in which we learn to perform actions that enable us to obtain desired outcomes, is central to many of these processes. Currently, our understanding of goal-directed learning in adolescence is itself in a state of transition, with the scientific community grappling with inconsistent results. When we examine metrics of goal-directed learning through the second decade of life, we find that many studies agree there are steady gains in performance in the teenage years, but others report that adolescent goal-directed learning is already adult-like, and some find adolescents can outperform adults. To explain the current variability in results, sophisticated experimental designs are being applied to test learning in different contexts. There is also increasing recognition that individuals of different ages and in different states will draw on different neurocognitive systems to support goal-directed learning. Through adoption of more nuanced approaches, we can be better prepared to recognize and harness adolescent strengths and to decipher the purpose (or goals) of adolescence itself.

Experimental biology can inform our understanding of food insecurity.

Food insecurity is a major public health issue. Millions of households worldwide have intermittent and unpredictable access to food and this experience is associated with greater risk for a host of negative health outcomes. While food insecurity is a contemporary concern, we can understand its effects better if we acknowledge that there are ancient biological programs that evolved to respond to the experience of food scarcity and uncertainty, and they may be particularly sensitive to food insecurity during development. Support for this conjecture comes from common findings in several recent animal studies that have modeled insecurity by manipulating predictability of food access in various ways. Using different experimental paradigms in different species, these studies have shown that experience of insecure access to food can lead to changes in weight, motivation and cognition. Some of these studies account for changes in weight through changes in metabolism, while others observe increases in feeding and motivation to work for food. It has been proposed that weight gain is an adaptive response to the experience of food insecurity as 'insurance' in an uncertain future, while changes in motivation and cognition may reflect strategic adjustments in foraging behavior. Animal studies also offer the opportunity to make in-depth controlled studies of mechanisms and behavior. So far, there is evidence that the experience of food insecurity can impact metabolic efficiency, reproductive capacity and dopamine neuron synapses. Further work on behavior, the central and peripheral nervous system, the gut and liver, along with variation in age of exposure, will be needed to better understand the full body impacts of food insecurity at different stages of development.

Importance of investing in adolescence from a developmental science perspective.

This review summarizes the case for investing in adolescence as a period of rapid growth, learning, adaptation, and formational neurobiological development. Adolescence is a dynamic maturational period during which young lives can pivot rapidly-in both negative and positive directions. Scientific progress in understanding adolescent development provides actionable insights into windows of opportunity during which policies can have a positive impact on developmental trajectories relating to health, education, and social and economic success. Given current global changes and challenges that affect adolescents, there is a compelling need to leverage these advances in developmental science to inform strategic investments in adolescent health.

Coming of age in the frontal cortex: The role of puberty in cortical maturation.

Across species, adolescence is a period of growing independence that is associated with the maturation of cognitive, social, and affective processing. Reorganization of neural circuits within the frontal cortex is believed to contribute to the emergence of adolescent changes in cognition and behavior. While puberty coincides with adolescence, relatively little is known about which aspects of frontal cortex maturation are driven by pubertal development and gonadal hormones. In this review, we highlight existing work that suggests puberty plays a role in the maturation of specific cell types in the medial prefrontal cortex (mPFC) of rodents, and highlight possible routes by which gonadal hormones influence frontal cortical circuit development.

Modeling changes in probabilistic reinforcement learning during adolescence.

In the real world, many relationships between events are uncertain and probabilistic. Uncertainty is also likely to be a more common feature of daily experience for youth because they have less experience to draw from than adults. Some studies suggest probabilistic learning may be inefficient in youths compared to adults, while others suggest it may be more efficient in youths in mid adolescence. Here we used a probabilistic reinforcement learning task to test how youth age 8-17 (N = 187) and adults age 18-30 (N = 110) learn about stable probabilistic contingencies. Performance increased with age through early-twenties, then stabilized. Using hierarchical Bayesian methods to fit computational reinforcement learning models, we show that all participants' performance was better explained by models in which negative outcomes had minimal to no impact on learning. The performance increase over age was driven by 1) an increase in learning rate (i.e. decrease in integration time scale); 2) a decrease in noisy/exploratory choices. In mid-adolescence age 13-15, salivary testosterone and learning rate were positively related. We discuss our findings in the context of other studies and hypotheses about adolescent brain development.

A basal ganglia circuit for evaluating action outcomes.

The basal ganglia, a group of subcortical nuclei, play a crucial role in decision-making by selecting actions and evaluating their outcomes. While much is known about the function of the basal ganglia circuitry in selection, how these nuclei contribute to outcome evaluation is less clear. Here we show that neurons in the habenula-projecting globus pallidus (GPh) in mice are essential for evaluating action outcomes and are regulated by a specific set of inputs from the basal ganglia. We find in a classical conditioning task that individual mouse GPh neurons bidirectionally encode whether an outcome is better or worse than expected. Mimicking these evaluation signals with optogenetic inhibition or excitation is sufficient to reinforce or discourage actions in a decision-making task. Moreover, cell-type-specific synaptic manipulations reveal that the inhibitory and excitatory inputs to the GPh are necessary for mice to appropriately evaluate positive and negative feedback, respectively. Finally, using rabies-virus-assisted monosynaptic tracing, we show that the GPh is embedded in a basal ganglia circuit wherein it receives inhibitory input from both striosomal and matrix compartments of the striatum, and excitatory input from the 'limbic' regions of the subthalamic nucleus. Our results provide evidence that information about the selection and evaluation of actions is channelled through distinct sets of basal ganglia circuits, with the GPh representing a key locus in which information of opposing valence is integrated to determine whether action outcomes are better or worse than expected.

Sex and Pubertal Status Influence Dendritic Spine Density on Frontal Corticostriatal Projection Neurons in Mice.

In humans, nonhuman primates, and rodents, the frontal cortices exhibit grey matter thinning and dendritic spine pruning that extends into adolescence. This maturation is believed to support higher cognition but may also confer psychiatric vulnerability during adolescence. Currently, little is known about how specific cell types in the frontal cortex mature or whether puberty plays a role in the maturation of some cell types but not others. Here, we used mice to characterize the spatial topography and adolescent development of cross-corticostriatal (cSTR) neurons that project through the corpus collosum to the dorsomedial striatum. We found that apical spine density on cSTR neurons in the medial prefrontal cortex decreased significantly between late juvenile (P29) and young adult time points (P60), with females exhibiting higher spine density than males at both ages. Adult males castrated prior to puberty onset had higher spine density compared to sham controls. Adult females ovariectomized before puberty onset showed greater variance in spine density measures on cSTR cells compared to controls, but their mean spine density did not significantly differ from sham controls. Our findings reveal that these cSTR neurons, a subtype of the broader class of intratelencephalic-type neurons, exhibit significant sex differences and suggest that spine pruning on cSTR neurons is regulated by puberty in male mice.

Prepubertal gonadectomy reveals sex differences in approach-avoidance behavior in adult mice.

Adolescence is a developmental period that is associated with physical, cognitive, and affective maturation and a time when sex biases in multiple psychiatric diseases emerge. While puberty onset marks the initiation of adolescence, it is unclear whether the pubertal rise in gonadal hormones generates sex differences in approach-avoidance behaviors that may impact psychiatric vulnerability. To examine the influence of pubertal development on adult behavior, we removed the gonads or performed sham surgery in male and female mice just prior to puberty onset and assessed performance in an odor-guided foraging task and anxiety-related behaviors in adulthood. We observed no significant sex differences in foraging or anxiety-related behaviors between intact adult male and female mice but found significant differences between adult male and female mice that had been gonadectomized (GDX) prior to puberty onset. GDX males failed to acquire the odor-guided foraging task, showed reduced locomotion, and exhibited increased anxiety-like behavior, while GDX females showed the opposite pattern of behavior. These data suggest that puberty may minimize rather than drive differences in approach-avoidance phenotypes in male and female mice.

Optical Fibers Functionalized with Single-Walled Carbon Nanotubes for Flexible Fluorescent Catecholamine Detection.

Despite the blockbuster popularity of drugs that act on catecholamine receptors, catecholamine dynamics in human health and disease remain an incomplete picture. Recent advances in fluorescent sensors have enabled unprecedented access to catecholamine dynamics in preclinical animal models, but the requirements of these technologies limit translational value for clinical diagnostics. Here, we present a flexible and convenient tool for fluorescent catecholamine detection by functionalizing optical fibers with single-walled carbon nanotube (SWNT)-based near-infrared catecholamine sensors (nIRCats), a form factor that has potential for more convenient and less invasive clinical translation. We show that these near-infrared functionalized (nIRF) fibers respond to dopamine in a biologically-relevant concentration range (10nM through 1 µM) with a mean ΔF/F0 of 0.022 through 0.411, with no statistically significant effect on signal magnitude after 16-hour exposure to human blood plasma. We further demonstrate the utility of these fibers in as little as 10 µL volumes of clinically relevant biofluids up to 24 weeks after preparation, with a ΔF/F0 of up to 0.059 through 1.127 for 10 nM through 1 µM dopamine. We also introduce a compact, mobile dual-near-infrared fiber photometry rig and demonstrate its success detecting dopamine with 0.005 ΔF/F0 in acute brain slices with nIRF fibers. Together, this fiber-based tool and photometry rig expand the toolbox of catecholamine detection technologies to a broader range of applications.

Explaining dopamine through prediction errors and beyond.

The most influential account of phasic dopamine holds that it reports reward prediction errors (RPEs). The RPE-based interpretation of dopamine signaling is, in its original form, probably too simple and fails to explain all the properties of phasic dopamine observed in behaving animals. This Perspective helps to resolve some of the conflicting interpretations of dopamine that currently exist in the literature. We focus on the following three empirical challenges to the RPE theory of dopamine: why does dopamine (1) ramp up as animals approach rewards, (2) respond to sensory and motor features and (3) influence action selection? We argue that the prediction error concept, once it has been suitably modified and generalized based on an analysis of each computational problem, answers each challenge. Nonetheless, there are a number of additional empirical findings that appear to demand fundamentally different theoretical explanations beyond encoding RPE. Therefore, looking forward, we discuss the prospects for a unifying theory that respects the diversity of dopamine signaling and function as well as the complex circuitry that both underlies and responds to dopaminergic transmission.

Nucleus accumbens dopamine release reflects Bayesian inference during instrumental learning.

Dopamine release in the nucleus accumbens has been hypothesized to signal reward prediction error, the difference between observed and predicted reward, suggesting a biological implementation for reinforcement learning. Rigorous tests of this hypothesis require assumptions about how the brain maps sensory signals to reward predictions, yet this mapping is still poorly understood. In particular, the mapping is non-trivial when sensory signals provide ambiguous information about the hidden state of the environment. Previous work using classical conditioning tasks has suggested that reward predictions are generated conditional on probabilistic beliefs about the hidden state, such that dopamine implicitly reflects these beliefs. Here we test this hypothesis in the context of an instrumental task (a two-armed bandit), where the hidden state switches repeatedly. We measured choice behavior and recorded dLight signals reflecting dopamine release in the nucleus accumbens core. Model comparison based on the behavioral data favored models that used Bayesian updating of probabilistic beliefs. These same models also quantitatively matched the dopamine measurements better than non-Bayesian alternatives. We conclude that probabilistic belief computation plays a fundamental role in instrumental performance and associated mesolimbic dopamine signaling.

Nucleus accumbens medium spiny neurons target non-dopaminergic neurons in the ventral tegmental area.

The midbrain ventral tegmental area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABA(A) or GABA(B) receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo. We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABA(A) receptors.

Experience-dependent and cell-type-specific spine growth in the neocortex.

Functional circuits in the adult neocortex adjust to novel sensory experience, but the underlying synaptic mechanisms remain unknown. Growth and retraction of dendritic spines with synapse formation and elimination could change brain circuits. In the apical tufts of layer 5B (L5B) pyramidal neurons in the mouse barrel cortex, a subset of dendritic spines appear and disappear over days, whereas most spines are persistent for months. Under baseline conditions, new spines are mostly transient and rarely survive for more than a week. Transient spines tend to be small, whereas persistent spines are usually large. Because most excitatory synapses in the cortex occur on spines, and because synapse size and the number of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are proportional to spine volume, the excitation of pyramidal neurons is probably driven through synapses on persistent spines. Here we test whether the generation and loss of persistent spines are enhanced by novel sensory experience. We repeatedly imaged dendritic spines for one month after trimming alternate whiskers, a paradigm that induces adaptive functional changes in neocortical circuits. Whisker trimming stabilized new spines and destabilized previously persistent spines. New-persistent spines always formed synapses. They were preferentially added on L5B neurons with complex apical tufts rather than simple tufts. Our data indicate that novel sensory experience drives the stabilization of new spines on subclasses of cortical neurons. These synaptic changes probably underlie experience-dependent remodelling of specific neocortical circuits.

Making sense of strengths and weaknesses observed in adolescent laboratory rodents.

During adolescence, rodents disperse from their natal site, find a new home, and navigate social relationships and threats. Although rats and mice in the laboratory cannot fully express these natural behaviors, they show striking changes in their affective and cognitive behavior across the adolescent period. In some laboratory-based behavior metrics, adolescent rodents fail to show the same behaviors expressed by adults, but in other metrics, adolescent behavioral performance is more robust or more flexible than at other ages. These data are often interpreted in light of proximate level analysis of development of neural circuits. It is also informative to attempt ultimate-level explanations and consider how sex and species-specific adolescent behavioral changes support dispersal, foraging, and social interactions in the wild.

Sex Differences in Pubertal Circadian and Ultradian Rhythmic Development Under Semi-naturalistic Conditions.

Biological rhythms in core body temperature (CBT) provide informative markers of adolescent development under controlled laboratory conditions. However, it is unknown whether these markers are preserved under more variable, semi-naturalistic conditions, and whether CBT may therefore prove useful in a real-world setting. To evaluate this possibility, we examined fecal steroid concentrations and CBT rhythms from pre-adolescence (p26) through early adulthood (p76) in intact male and female Wistar rats under natural light and climate at the Stephen Glickman Field Station for the Study of Behavior, Ecology and Reproduction. Despite greater environmental variability, CBT markers of pubertal onset and its rhythmic progression were comparable with those previously reported in laboratory conditions in female rats and extend actigraphy-based findings in males. Specifically, sex differences emerged in CBT circadian rhythm (CR) power and amplitude prior to pubertal onset and persisted into early adulthood, with females exhibiting elevated CBT and decreased CR power compared with males. Within-day (ultradian rhythm [UR]) patterns also exhibited a pronounced sex difference associated with estrous cyclicity. Pubertal onset, defined by vaginal opening, preputial separation, and sex steroid concentrations, occurred later than previously reported under lab conditions for both sexes. Vaginal opening and increased fecal estradiol concentrations were closely tied to the commencement of 4-day oscillations in CBT and UR power. By contrast, preputial separation and the first rise in testosterone concentration were not associated with adolescent changes to CBT rhythms in male rats. Together, males and females exhibited unique temporal patterning of CBT and sex steroids across pubertal development, with tractable associations between hormonal concentrations, external development, and temporal structure in females. The preservation of these features outside the laboratory supports CBT as a strong candidate for translational pubertal monitoring under semi-naturalistic conditions in females.

Reinforcement learning and Bayesian inference provide complementary models for the unique advantage of adolescents in stochastic reversal.

During adolescence, youth venture out, explore the wider world, and are challenged to learn how to navigate novel and uncertain environments. We investigated how performance changes across adolescent development in a stochastic, volatile reversal-learning task that uniquely taxes the balance of persistence and flexibility. In a sample of 291 participants aged 8-30, we found that in the mid-teen years, adolescents outperformed both younger and older participants. We developed two independent cognitive models, based on Reinforcement learning (RL) and Bayesian inference (BI). The RL parameter for learning from negative outcomes and the BI parameters specifying participants' mental models were closest to optimal in mid-teen adolescents, suggesting a central role in adolescent cognitive processing. By contrast, persistence and noise parameters improved monotonically with age. We distilled the insights of RL and BI using principal component analysis and found that three shared components interacted to form the adolescent performance peak: adult-like behavioral quality, child-like time scales, and developmentally-unique processing of positive feedback. This research highlights adolescence as a neurodevelopmental window that can create performance advantages in volatile and uncertain environments. It also shows how detailed insights can be gleaned by using cognitive models in new ways.

Transient food insecurity during the juvenile-adolescent period affects adult weight, cognitive flexibility, and dopamine neurobiology.

A major challenge for neuroscience, public health, and evolutionary biology is to understand the effects of scarcity and uncertainty on the developing brain. Currently, a significant fraction of children and adolescents worldwide experience insecure access to food. The goal of our work was to test in mice whether the transient experience of insecure versus secure access to food during the juvenile-adolescent period produced lasting differences in learning, decision-making, and the dopamine system in adulthood. We manipulated feeding schedules in mice from postnatal day (P)21 to P40 as food insecure or ad libitum and found that when tested in adulthood (after P60), males with different developmental feeding history showed significant differences in multiple metrics of cognitive flexibility in learning and decision-making. Adult females with different developmental feeding history showed no differences in cognitive flexibility but did show significant differences in adult weight. We next applied reinforcement learning models to these behavioral data. The best fit models suggested that in males, developmental feeding history altered how mice updated their behavior after negative outcomes. This effect was sensitive to task context and reward contingencies. Consistent with these results, in males, we found that the two feeding history groups showed significant differences in the AMPAR/NMDAR ratio of excitatory synapses on nucleus-accumbens-projecting midbrain dopamine neurons and evoked dopamine release in dorsal striatal targets. Together, these data show in a rodent model that transient differences in feeding history in the juvenile-adolescent period can have significant impacts on adult weight, learning, decision-making, and dopamine neurobiology.

The interpretation of computational model parameters depends on the context.

Reinforcement Learning (RL) models have revolutionized the cognitive and brain sciences, promising to explain behavior from simple conditioning to complex problem solving, to shed light on developmental and individual differences, and to anchor cognitive processes in specific brain mechanisms. However, the RL literature increasingly reveals contradictory results, which might cast doubt on these claims. We hypothesized that many contradictions arise from two commonly-held assumptions about computational model parameters that are actually often invalid: That parameters generalize between contexts (e.g. tasks, models) and that they capture interpretable (i.e. unique, distinctive) neurocognitive processes. To test this, we asked 291 participants aged 8-30 years to complete three learning tasks in one experimental session, and fitted RL models to each. We found that some parameters (exploration / decision noise) showed significant generalization: they followed similar developmental trajectories, and were reciprocally predictive between tasks. Still, generalization was significantly below the methodological ceiling. Furthermore, other parameters (learning rates, forgetting) did not show evidence of generalization, and sometimes even opposite developmental trajectories. Interpretability was low for all parameters. We conclude that the systematic study of context factors (e.g. reward stochasticity; task volatility) will be necessary to enhance the generalizability and interpretability of computational cognitive models.

Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task.

The dorsomedial striatum (DMS) plays a key role in action selection, but less is known about how direct and indirect pathway spiny projection neurons (dSPNs and iSPNs, respectively) contribute to choice rejection in freely moving animals. Here, we use pathway-specific chemogenetic manipulation during a serial choice foraging task to test the role of dSPNs and iSPNs in learned choice rejection. We find that chemogenetic activation, but not inhibition, of iSPNs disrupts rejection of nonrewarded choices, contrary to predictions of a simple "select/suppress" heuristic. Our findings suggest that iSPNs' role in stopping and freezing does not extend in a simple fashion to choice rejection in an ethological, freely moving context. These data may provide insights critical for the successful design of interventions for addiction or other conditions in which it is desirable to strengthen choice rejection.