Relying almost exclusively on their acute sense of touch, tactileforaging birds can feed in murky water, but the cellular mechanism is unknown. Mechanical stimuli activate specialized cutaneous end organs in the bill, innervated by trigeminal afferents. We report that trigeminal ganglia (TG) of domestic and wild tactileforaging ducks exhibit numerical expansion of large-diameter mechanoreceptive neurons expressing the mechano-gated ion channel Piezo2. These features are not found in visually foraging birds. Moreover, in the duck, the expansion of mechanoreceptors occurs at the expense of thermosensors. Direct mechanical stimulation of duck TG neurons evokes high-amplitude depolarizing current with a low threshold of activation, high signal amplification gain, and slow kinetics of inactivation. Together, these factors contribute to efficient conversion of light mechanical stimuli into neuronal excitation. Our results reveal an evolutionary strategy to hone tactile perception in vertebrates at the level of primary afferents.A nimals with acute sense of touch provide an opportunity to study cellular and molecular principles of mechanoreception from an unconventional perspective (1, 2). Tactile-foraging waterfowl of the Anatidae family rely on their acute sense of touch rather than vision to find food. Using a complex array of highly coordinated feeding techniques-straining, pecking, and dabbling-they can selectively collect gastropods, worms, crustaceans, and plant matter even in murky water with high precision and efficiency. This highly discriminatory feeding behavior relies on the acquisition and rapid processing of sensory information coming from numerous mechanoreceptors in the bill (3).Mechanoreceptors are cell-neurite complexes that specialize in the detection of diverse mechanical stimuli. The most numerous mechanoreceptors in the bill skin of Anatidae birds are Herbst and Grandry corpuscles, which are present at high density (up to 150 receptors per square millimeter) 50-100 μm below the epidermis of dorsal and ventral surfaces of the upper and lower bill (4, 5). The mechanoreceptors are innervated by rapidly adapting primary afferents projecting from the trigeminal ganglia (TG) (Fig. 1A) and are best tuned to detect vibration and velocity (6-10). In this sense, Herbst and Grandry organs appear functionally homologous to the mammalian Pacinian and Meissner corpuscles, respectively. Following stimulus detection, mechanosensory information is processed in the trigeminal nucleus (PrV) of the brainstem. In tactile foragers, such as ducks, PrV accounts for a significantly larger fraction of total brain volume compared with visual foragers, such as chicken (11). This augmented neural representation reflects the need to process the complex and abundant tactile information from the primary afferents of the trigeminal nerve. However, even though the general layout of the mechanosensory system is well established, the contribution of primary afferents in stimulus detection is unclear.In rodents, over 80% of somatose...

Hibernating mammals possess a unique ability to reduce their body temperature to ambient levels, which can be as low as −2.9°C, by active down-regulation of metabolism. Despite such a depressed physiologic phenotype, hibernators still maintain activity in their nervous systems, as evidenced by their continued sensitivity to auditory, tactile, and thermal stimulation. The molecular mechanisms that underlie this adaptation remain unknown. We report, using differential transcriptomics alongside immunohistologic and biochemical analyses, that neurons from thirteen-lined ground squirrels (Ictidomys tridecemlineatus) express mitochondrial uncoupling protein 1 (UCP1). The expression changes seasonally, with higher expression during hibernation compared with the summer active state. Functional and pharmacologic analyses show that squirrel UCP1 acts as the typical thermogenic protein in vitro. Accordingly, we found that mitochondria isolated from torpid squirrel brain show a high level of palmitate-induced uncoupling. Furthermore, torpid squirrels during the hibernation season keep their brain temperature significantly elevated above ambient temperature and that of the rest of the body, including brown adipose tissue. Together, our findings suggest that UCP1 contributes to local thermogenesis in the squirrel brain, and thus supports nervous tissue function at low body temperature during hibernation.T hirteen-lined ground squirrels (Ictidomys tridecemlineatus) are obligatory hibernating mammals. They are found across a wide range of latitudes, from southern Canada to the Gulf of Mexico. In northern habitats with long winters and limited food resources, ground squirrels breed only once a year, in late spring, and then hibernate in underground burrows from October to April. Hibernation consists of cycling between bouts of torpor and brief interbout arousal periods, each usually lasting less than 24 h (1, 2).During the long hibernation season, torpid animals undergo dramatic perturbations, including reduction in heart, respiratory, and overall metabolic rates, as well as decreases in core body temperature from 37°C to just above ambient temperature (often as low as 1-5°C) (2). Despite such a depressed physiologic phenotype, torpid animals remain sensitive to their environment (3). For example, during extreme winters, when ambient burrow temperatures reach the freezing point of water, most hibernating mammals increase metabolic activity and warm up as a safety precaution to prevent freezing (4). Similarly, arousal can be triggered by sound, touch, or a sudden increase in ambient temperature (3, 5). Thus, hibernating animals maintain activity in their peripheral and central nervous systems. Indeed, physiologic experiments conducted on nerve fibers isolated from torpid hamsters and squirrels demonstrated the ability to generate action potentials at temperatures prohibitively low for their nonhibernating relatives (i.e., rats, mice) (6-8).Deeply hibernating animals can keep their brain temperatures elevated above ambient by seve...

Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it also mediates DNA damage repair essential to proliferating neural progenitor cells (NPCs). Here, we uncover molecularly dissociable roles for nucleosome remodeler Ino80 in chromatin-mediated transcriptional regulation and genome maintenance in corticogenesis. We find that conditional Ino80 deletion from cortical NPCs impairs DNA double-strand break (DSB) repair, triggering p53-dependent apoptosis and microcephaly. Using an in vivo DSB repair pathway assay, we find that Ino80 is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from Ino80 function in YY1-associated transcription. Unexpectedly, sensitivity to loss of Ino80 -mediated HR is dependent on NPC division mode: Ino80 deletion leads to unrepaired DNA breaks and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions. This division mode dependence is phenocopied following conditional deletion of HR gene Brca2 . Thus, distinct modes of NPC division have divergent requirements for Ino80 -dependent HR DNA repair.

Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation (“handshake”), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.

Histone variants, which can be expressed outside of S-phase and deposited DNA synthesis-independently, provide long-term histone replacement in postmitotic cells, including neurons. Beyond replenishment, histone variants also play active roles in gene regulation by modulating chromatin states or enabling nucleosome turnover. Here, we uncover crucial roles for the histone H3 variant H3.3 in neuronal development. We find that newborn cortical excitatory neurons, which have only just completed replication-coupled deposition of canonical H3.1 and H3.2, substantially accumulate H3.3 immediately postmitosis. Codeletion of H3.3-encoding genes H3f3a and H3f3b from newly postmitotic neurons abrogates H3.3 accumulation, markedly alters the histone posttranslational modification landscape, and causes widespread disruptions to the establishment of the neuronal transcriptome. These changes coincide with developmental phenotypes in neuronal identities and axon projections. Thus, preexisting, replication-dependent histones are insufficient for establishing neuronal chromatin and transcriptome; de novo H3.3 is required. Stage-dependent deletion of H3f3a and H3f3b from 1) cycling neural progenitor cells, 2) neurons immediately postmitosis, or 3) several days later, reveals the first postmitotic days to be a critical window for de novo H3.3. After H3.3 accumulation within this developmental window, codeletion of H3f3a and H3f3b does not lead to immediate H3.3 loss, but causes progressive H3.3 depletion over several months without widespread transcriptional disruptions or cellular phenotypes. Our study thus uncovers key developmental roles for de novo H3.3 in establishing neuronal chromatin, transcriptome, identity, and connectivity immediately postmitosis that are distinct from its role in maintaining total histone H3 levels over the neuronal lifespan.