Peripheral nerves are organized into discrete compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium, a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a neuropathy with similar defects. Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization in mice of both genders. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs noncanonically (i.e., independent of hedgehog signaling). Gli1 and Dhh also ...

Neuronal activity in the prefrontal cortex (PFC) controls dominance hierarchies in groups of animals. Dopamine (DA) strongly modulates PFC activity mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs). Still, it is unclear how these two subpopulations of DA receptor-expressing neurons in the PFC regulate social dominance hierarchy. Here, we demonstrate distinct roles for prefrontal D1R- and D2R-expressing neurons in establishing social hierarchy, with D1R+ neurons determining dominance and D2R+ neurons for subordinate. Ex vivo whole-cell recordings revealed that the dominant status of male mice correlates with rectifying AMPAR transmission and stronger excitatory synaptic strength onto D1R+ neurons in PFC pyramidal neurons. In contrast, the submissive status is associated with higher neuronal excitability in D2R+ neurons. Moreover, simultaneous manipulations of synaptic efficacy of D1R+ neurons in dominant male mice and neuronal excitability of D2R+ neurons of their male subordinates switch their dom...

Much animal learning is slow, with cumulative changes in behavior driven by reward prediction errors. When the abstract structure of a problem is known, however, both animals and formal learning models can rapidly attach new items to their roles within this structure, sometimes in a single trial. Frontal cortex is likely to play a key role in this process. To examine information seeking and use in a known problem structure, we trained monkeys in an explore/exploit task, requiring the animal first to test objects for their association with reward, then, once rewarded objects were found, to reselect them on further trials for further rewards. Many cells in the frontal cortex showed an explore/exploit preference aligned with one-shot learning in the monkeys' behavior: the population switched from an explore state to an exploit state after a single trial of learning but partially maintained the explore state if an error indicated that learning had failed. Binary switch from explore to exploit was not explained...

Recent research suggests that episodic memory is associated with systematic differences in the localization of neural activity observed during memory encoding and retrieval. The retrieval-related anterior shift is a phenomenon whereby the retrieval of a stimulus event (e.g., a scene image) is associated with a peak neural response which is localized more anteriorly than the response elicited when the stimulus is experienced directly. Here, we examine whether the magnitude of the anterior shift, i.e., the distance between encoding- and retrieval-related response peaks, is moderated by age, and also whether the shift is associated with memory performance. Younger and older human subjects of both sexes underwent fMRI as they completed encoding and retrieval tasks on word-face and word-scene pairs. We localized peak scene- and face-selectivity for each individual participant within the face-selective precuneus (PCU) and in three scene-selective (parahippocampal place area [PPA], medial place area [MPA], occipi...

Amacrine cells, inhibitory interneurons of the retina, feature synaptic inputs and outputs in close proximity throughout their dendritic trees, making them notable exceptions to prototypical somato-dendritic integration with output transmitted via axonal action potentials. The extent of dendritic compartmentalization in amacrine cells with widely differing dendritic tree morphology, however, is largely unexplored. Combining compartmental modeling, dendritic Ca2+ imaging, targeted microiontophoresis and multi-electrode patch-clamp recording (voltage and current clamp, capacitance measurement of exocytosis), we investigated integration in the AII amacrine cell, a narrow-field electrically coupled interneuron that participates in multiple, distinct microcircuits. Physiological experiments were performed with in vitro slices prepared from retinas of both male and female rats. We found that the morphology of the AII enables simultaneous local and global integration of inputs targeted to different dendritic regi...

GABAB receptors in habenula cholinergic neurons mediate strong presynaptic excitation and control aversive memory expression. K+ channel tetramerization domain (KCTD) proteins are key interacting partners of GABAB receptors; it remains unclear whether and how KCTDs contribute to GABAB excitatory signaling. Here, we show that KCTD8 and KCTD12 in these neurons facilitate the GABAB receptors expression in axonal terminals and contribute to presynaptic excitation by GABAB receptors. Genetically knocking out KCTD8/12/16 , or KCTD8/12 , but not other combinations of the three KCTD isoforms, substantially reduced GABAB receptors–mediated potentiation of glutamate release and presynaptic Ca2+ entry in response to axonal stimulation, whereas they had no effect on GABAB-mediated inhibition in the somata of cholinergic neurons within the habenulo-interpeduncular pathway in mice of either sex. The physiological phenotypes were associated with a significant decrease in the GABAB expression within the axonal terminals b...

Humans rely on precise proprioceptive feedback from our muscles to perform daily activities, which is important in both the acquisition and execution of movements. Somatosensory input from the body shapes motor learning through central processes, as demonstrated for tasks using the arm, under active (self-generated) and passive conditions. Presently, we investigated whether passive movement training of the ankle increased proprioceptive acuity (psychophysical experiment) and whether it changed the peripheral proprioceptive afferent signal (microneurography experiment). In the psychophysical experiment, the ankle of 32 healthy human participants was moved passively using pairs of ramp-and-hold movements in different directions. In a pre-training test, participants made judgements about the movement direction in a two-alternative forced choice paradigm. Participants then underwent passive movement training, but only half were cued for learning, where a reference position was signaled by a sound and the parti...

Proper somatosensory circuit assembly is critical for processing somatosensory stimuli and for responding accordingly. In comparison to other sensory circuits (e.g., olfactory and visual), somatosensory circuits have unique anatomy and function. However, understanding of somatosensory circuit development lags far behind that of other sensory systems. For example, there are few identified transcription factors required for integration of interneurons into functional somatosensory circuits. Here, as a model, we examine one type of somatosensory interneuron, Even-skipped expressing Laterally placed interneurons (ELs) of the Drosophila larval nerve cord. Even-skipped (Eve) is a highly conserved, homeodomain transcription factor known to play a role in cell fate specification and neuronal axon guidance. Because marker genes are often functionally important in the cell types they define, we deleted eve specifically from EL interneurons. On the cell biological level, using single neuron labeling, we find eve play...

Oxytocin (Oxt) controls reproductive physiology and various kinds of social behaviors, but the exact contribution of Oxt to different components of parental care still needs to be determined. Here we illustrate the neuroanatomical relations of the parental nurturing-induced neuronal activation with magnocellular oxytocin neurons and fibers in the medial preoptic area (MPOA), the brain region critical for parental and alloparental behaviors. We utilized genetically-targeted mouse lines for Oxt , oxytocin receptor (Oxtr) , vasopressin receptor 1a (Avpr1a) , vasopressin receptor 1b (Avpr1b), and thyrotropin-releasing hormone (Trh) to systematically examine the role of Oxt-related signaling in pup-directed behaviors. The Oxtr - Avpr1a - Avpr1b triple knockout (TKO), and Oxt - Trh - Avpr1a - Avpr1b quadruple KO (QKO) mice were grossly healthy and fertile, except for their complete deficiency in milk ejection and modest deficiency in parturition secondary to maternal loss of the Oxt or Oxtr genes. In our minimal...