The subthalamic nucleus (STN) is an essential component of the basal ganglia and has long been considered to be a part of the ventral thalamus. However, recent neurodevelopmental data indicated that this nucleus is of hypothalamic origin which is now commonly acknowledged. In this work, we aimed to verify whether the inclusion of the STN in the hypothalamus could influence the way we understand and conduct research on the organization of the whole ventral and posterior diencephalon. Developmental and neurochemical data indicate that the STN is part of a larger glutamatergic posterior hypothalamic region that includes the premammillary and mammillary nuclei. The main anatomic characteristic common to this region involves the convergent cortical and pallidal projections that it receives, which is based on the model of the hyperdirect and indirect pathways to the STN. This whole posterior hypothalamic region is then integrated into distinct functional networks that interact with the ventral mesencephalon to a...

Spatial orientation memory plays a crucial role in animal navigation. Recent studies of tethered Drosophila melanogaster (fruit fly) in a virtual reality setting showed that the head direction is encoded in the form of an activity bump, i.e., localized neural activity, in the torus-shaped ellipsoid body (EB). However, how this system is involved in orientation working memory is not well understood. We investigated this question using free moving flies ( D. melanogaster ) in a spatial orientation memory task by manipulating two EB subsystems, C and P circuits, which are hypothesized for stabilizing and updating the activity bump, respectively. To this end, we suppressed or activated two types of inhibitory ring neurons (EIP and P) which innervate EB, and we discovered that manipulating the two inhibitory neuron types produced distinct behavioral deficits, suggesting specific roles of the inhibitory neurons in coordinating the stabilization and updating functions of the EB circuits. We further elucidate the ...

The ability to adapt under significant adversity, defined as psychological resilience, is instrumental in preventing stress-related disorders. An important aspect of resilience is the capacity to endure affective distress when in pursuit of goals, also known as distress tolerance. Evidence that links intrinsic baseline interactions within large-scale functional networks with performance under distress remains missing. We hypothesized that the anterior cingulate cortex (ACC) may engage in distress tolerance because of its involvement in attention and emotion regulation. Accordingly, we tested whether behavioral performance under distress is associated with baseline resting-state ACC functional connectivity (FC). Distress tolerance was measured in 97 participants using the behavioral indicator of resiliency to distress (BIRD) task. Analyses contrasted participants who quit the task before its designated termination ( n  = 51) with those who persisted throughout it ( n  = 46). Seed-based FC analysis indicated...

Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR...

Knee joint trauma can cause an osteochondral defect (OD), a risk factor for osteoarthritis (OA) and cause of debilitating pain in patients. Rodent OD models are less translatable because of their smaller joint size and open growth plate. This study proposes sheep as a translationally relevant model to understand the neuronal basis of OD pain. A unilateral 6-mm deep OD was induced in adult female sheep. Two to six weeks after operation, lumbar dorsal root ganglia (DRG) neurons were collected from the contralateral (Ctrl) and OD side of operated sheep. Functional assessment of neuronal excitability and activity of the pain-related ion channels transient receptor potential vanilloid receptor 1 (TRPV1) and P2X3 was conducted using electrophysiology and Ca2+ imaging. Immunohistochemistry was used to verify expression of pain-related proteins. We observed that an increased proportion of OD DRG neurons (sheep, N  = 3; Ctrl neurons, n  = 15, OD neurons, n  = 16) showed spontaneous electrical excitability (Ctrl: 20...

Opsin 3 ( Opn3 ) is highly expressed in the adult brain, however, information for spatial and temporal expression patterns during embryogenesis is significantly lacking. Here, an Opn3 -eGFP reporter mouse line was used to monitor cell body expression and axonal projections during embryonic and early postnatal to adult stages. By applying 2D and 3D fluorescence imaging techniques, we have identified the onset of Opn3 expression, which predominantly occurred during embryonic stages, in various structures during brain/head development. In addition, this study defines over twenty Opn3 -eGFP-positive neural structures never reported before. Opn3 -eGFP was first observed at E9.5 in neural regions, including the ganglia that will ultimately form the trigeminal, facial and vestibulocochlear cranial nerves (CNs). As development proceeds, expanded Opn3 -eGFP expression coincided with the formation and maturation of critical components of the central and peripheral nervous systems (CNS, PNS), including various motor-...

The mouse vomeronasal system controls several social behaviors. Pheromones and other social cues are detected by sensory neurons in the vomeronasal organ (VNO). Stimuli activate a transduction cascade that leads to membrane potential depolarization, increase in cytosolic Ca2+ level, and increased firing. The Ca2+-activated chloride channels TMEM16A and TMEM16B are co-expressed within microvilli of vomeronasal neurons, but their physiological role remains elusive. Here, we investigate the contribution of each of these channels to vomeronasal neuron firing activity by comparing wild-type (WT) and knock-out (KO) mice. Performing loose-patch recordings from neurons in acute VNO slices, we show that spontaneous activity is modified by Tmem16a KO, indicating that TMEM16A, but not TMEM16B, is active under basal conditions. Upon exposure to diluted urine, a rich source of mouse pheromones, we observe significant changes in activity. Vomeronasal sensory neurons (VSNs) from Tmem16a cKO and Tmem16b KO mice show short...

Behavioral flexibility enables the ability to adaptively respond to changes in contingency requirements to maintain access to desired outcomes, and deficits in behavioral flexibility have been documented in many psychiatric disorders. Previous research has shown a correlation between behavioral flexibility measured in a reversal learning test and Syn3 , the gene encoding synapsin III, which negatively regulates phasic dopamine release. Syn3 expression in the hippocampus, striatum, and neocortex is reported to be negatively correlated with reversal learning performance, so here, we used a global knock-out line to investigate reversal learning in mice homozygous wild type, heterozygous null, and homozygous null for the Syn3 gene. Compared with wild-type animals, we found a reversal-specific effect of genetic Syn3 deficiency that resulted in a greater proportional increase in trials required to reach a preset performance criterion during contingency reversal, despite no observed genotype effects on the abilit...

Biological neural networks operate at several levels of granularity, from the individual neuron to local neural circuits to networks of thousands of cells. The daily oscillation of the brain’s master clock in the suprachiasmatic nucleus (SCN) rests on a yet to be identified network of connectivity among its ∼20,000 neurons. The SCN provides an accessible model to explore neural organization at several levels of organization. To relate cellular to local and global network behaviors, we explore network topology by examining SCN slices in three orientations using immunochemistry, light and confocal microscopy, real-time imaging, and mathematical modeling. Importantly, the results reveal small local groupings of neurons that form intermediate structures, here termed “phaseoids,” which can be identified through stable local phase differences of varying magnitude among neighboring cells. These local differences in phase are distinct from the global phase relationship, namely that between individual cells and the...

Retinoic acid (RA), a metabolite of vitamin A, has many physiological functions, and mounting evidence points to important roles in cognition. In vitro experiments indicate that RA is involved in homeostatic synaptic scaling in the hippocampus, which supports overall network stability during learning. It has been previously determined that disrupted RA signaling in the hippocampus causes deterioration of memory, that RA signaling declines with age in brain, and that application of RA reverses this decline. Here, we explore whether RA signaling is altered in an animal model of neurocognitive aging. We used a Morris water maze protocol to study cognitive decline in aged rats, which assesses hippocampus-dependent spatial memory and reveals substantial interindividual differences in aged animals. Aged unimpaired (AU) rats perform on par with young (Y), while aged impaired (AI) animals exhibit spatial memory deficits. We show that the major substrate for RA, retinol binding protein 4 (RBP4), is decreased in AU ...