When faced with multiple potential movement options, individuals either reach directly to one of the options, or initiate a reach intermediate between the options. It remains unclear why people generate these two types of behaviors. Using the go-before-you-know task (commonly used to study behavior under choice uncertainty) in humans, we examined two key questions. First, do these two types of responses actually reflect distinct movement strategies? If so, the relative desirability (i.e., weighing the success likelihood versus the attainable reward) of the two target options would not need to be computed identically for direct and intermediate reaches. We showed that indeed, when reward and success likelihood differed between the two options, reach direction was preferentially biased toward different directions for direct versus intermediate reaches. Importantly, this suggests that the computation of subjective values depends on the choice of movement strategy. Second, what drives individual differences in...

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), are implicit in causing obesity. Mutations that reduce BDNF and TrkB expression are associated with obesity in humans and mice. Recently, it was reported that Bdnf gene deletion in the neurons of the paraventricular hypothalamus (PVH) caused positive energy balance and severe obesity in the form of hyperphagia, impaired adaptive thermogenesis, and decreased energy expenditure. Thus, we hypothesize that activation of these neurons will have the opposite effect and provide an opportunity for long-lasting obesity treatment. To specifically activate BDNF-expressing PVH (PVHBDNF) neurons, we injected Cre-dependent adeno-associated virus expressing the excitatory DREADD hM3Dq bilaterally into the PVH of Bdnf2A-Cre/+ knockin mice and then administered clozapine-n-oxide. Using this technique, we demonstrated that acute activation of these neurons rapidly decreased normal nocturnal feeding and fasting-induced feeding in...

Cannabinoid receptor 1 (CB1R) has strong effects on neurogenesis and axon pathfinding in the prenatal brain. Endocannabinoids that activate CB1R are abundant in the early postnatal brain and in mother’s milk, but few studies have investigated their function in newborns. We examined postnatal CB1R expression in the major striatonigral circuit from striosomes of the striatum to the dopamine-containing neurons of the substantia nigra. CB1R enrichment was first detectable between postnatal days 5 and 7, and this timing coincided with the formation of ‘striosome-dendron bouquets’, the elaborate anatomical structures by which striosomal neurons control dopaminergic cell activity through inhibitory synapses. In Cnr1−/− knockouts lacking CB1R expression, striosome-dendron bouquets were markedly disorganized by postnatal day 11 and at adulthood, suggesting a postnatal pathfinding connectivity function for CB1R in connecting striosomal axons and dopaminergic neurons analogous to CB1R’s prenatal function in other bra...

Humans can perform complex movements with speed and agility in the face of constantly changing task demands. To accomplish this, motor plans are adapted to account for errors in our movements due to changes in our body (e.g., growth or injury) or in the environment (e.g., walking on sand vs. ice). It has been suggested that adaptation that occurs in response to changes in the state of our body will generalize across different movement contexts and environments, whereas adaptation that occurs with alterations in the external environment will be context-specific. Here we asked if the ability to form generalizable versus context-specific motor memories develops during childhood. We performed a cross-sectional study of context-specific locomotor adaptation in 35 children (3-18 years old) and 7 adults (19-31 years old). Subjects first adapted their gait and learned a new walking pattern on a split-belt treadmill, which has two belts that move each leg at a different speed. Then, subjects walked overground to as...

The neural circuits that support human cognition are a topic of enduring interest. Yet, there are limited tools available to map human brain circuits in the human and non-human primate brain. We harnessed high-resolution diffusion MR tractography, anatomic, and transcriptomic data from individuals of either sex to investigate the evolution and development of frontal cortex circuitry. We applied machine learning to RNA sequencing data to find corresponding ages between humans and macaques and to compare the development of circuits across species. We transcriptionally defined neural circuits by testing for associations between gene expression and white matter maturation. We then considered transcriptional and structural growth to test whether frontal cortex circuit maturation is unusually extended in humans relative to other species. We also considered gene expression and high-resolution diffusion MR tractography of adult brains to test for cross-species variation in frontal cortex circuits. We found that fr...

Brain size significantly impacts the organization of white matter fibers. Fiber length scaling – the degree to which fiber length varies according to brain size – was overlooked. We investigated how fiber lengths within the corpus callosum, the most prominent white matter tract, vary according to brain size. The results showed substantial variation in length scaling among callosal fibers, replicated in two large healthy cohorts (∼2000 human subjects, including both sexes). The underscaled callosal fibers mainly connected the precentral gyrus and parietal cortices, whereas the overscaled callosal fibers mainly connected the prefrontal cortices. The variation in such length scaling was biologically meaningful: larger scaling corresponded to larger neurite density index but smaller fractional anisotropy values; cortical regions connected by the callosal fibers with larger scaling were more lateralized functionally as well as phylogenetically and ontogenetically more recent than their counterparts. These findi...

Many hippocampal CA1 pyramidal cells function as place cells, increasing their firing rate when a specific place field is traversed. The dependence of CA1 place cell firing on position within the place field is asymmetric. We investigated the source of this asymmetry by injecting triangular depolarizing current ramps to approximate the spatially-tuned, temporally-diffuse depolarizing synaptic input received by these neurons while traversing a place field. Ramps were applied to CA1 pyramidal neurons from male rats in vitro (slice electrophysiology) and in silico (multi-compartmental NEURON model). Under control conditions, CA1 neurons fired more action potentials at higher frequencies on the up-ramp versus the down-ramp. This effect was more pronounced for dendritic compared to somatic ramps. We incorporated a four-state Markov scheme for NaV1.6 channels into our model and calibrated the spatial dependence of long-term inactivation according to the literature; this spatial dependence was sufficient to expla...

Emerging evidence shows that spontaneous synaptic transmission plays crucial roles on neuronal functions through presynaptic molecular mechanisms distinct from that of action potential (AP)-evoked transmission. However, whether the synaptic vesicle (SV) population undergoing the two forms of transmission is segregated remains controversial due in part to the conflicting results observed in cultured neurons. Here we address this issue in intact neuromuscular synapses using transgenic zebrafish larvae expressing two different indicators targeted in the SVs: a pH-sensitive fluorescent protein, pHluorin, and a tag protein, HaloTag. By establishing a quantitative measure of recycled SV fractions, we found that approximately 85% of SVs were mobilized by high-frequency AP firings. In contrast, spontaneously recycling SVs were mobilized only from <8% of SVs with a time constant of 45 min at 25°C, although prolonged AP inhibition mobilized an additional population with a delayed onset. The mobilization of the early...

The opioid epidemic is a rapidly evolving societal issue driven, in part, by a surge in synthetic opioid use. A rise in fentanyl use among pregnant women has led to a 40-fold increase in the number of perinatally-exposed infants in the past decade. These children are more likely to develop mood- and somatosensory-related conditions later in life, suggesting that fentanyl may permanently alter neural development. Here, we examined the behavioral and synaptic consequences of perinatal fentanyl exposure in adolescent male and female C57BL/6J mice and assessed the therapeutic potential of environmental enrichment to mitigate these effects. Dams were given ad libitum access to fentanyl (10 µg/mL, per os ) across pregnancy and until weaning (PD 21). Perinatally-exposed adolescent mice displayed hyperactivity (PD 45), enhanced sensitivity to anxiogenic environments (PD 46), and sensory maladaptation (PD 47) – sustained behavioral effects that were completely normalized by environmental enrichment (PD 21-45). Addi...

Opioid use by pregnant women results in neonatal opioid withdrawal syndrome (NOWS) and lifelong neurobehavioral deficits including language impairments. Animal models of NOWS show impaired performance in a two-tone auditory discrimination task, suggesting abnormalities in sensory processing in the auditory cortex. To investigate the consequences of perinatal opioid exposure on auditory cortex circuits, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (P) 21. We then used in vivo 2-photon Ca2+ imaging in adult animals of both sexes to investigate how primary auditory cortex (A1) function was altered. Perinatally exposed animals showed fewer sound-responsive neurons in A1, and the remaining sound-responsive cells exhibited lower response amplitudes but normal frequency selectivity and stimulus-specific adaptation. Populations of nearby layer 2/3 (L2/3) cells in exposed animals showed reduced correlated activity, suggesting a re...