For proper execution of goal-directed behaviors, individuals require both a general representation of the goal and an ability to monitor their own progress toward that goal. Here, we examine how dorsomedial striatum (DMS), a region pivotal for forming associations among stimuli, actions, and outcomes, encodes the execution of goal-directed action sequences that require self-monitoring of behavior. We trained rats to complete a sequence of at least five consecutive lever presses (without visiting the reward port) to obtain a reward and recorded the activity of individual cells in DMS while rats performed the task. We found that the pattern of DMS activity gradually changed during the execution of the sequence, permitting accurate decoding of sequence progress from neural activity at a population level. Moreover, this sequence-related activity was blunted on trials where rats did not complete a sufficient number of presses. Overall, these data suggest a link between DMS activity and the execution of behavior...

The lateral septum (LS) is implicated as a hub that regulates a variety of affects, such as reward, feeding, anxiety, fear, sociability, and memory. However, it remains unclear how the LS, previously treated as a structure of homogeneity, exhibits such multifaceted functions. Emerging evidence suggests that different functions of the LS are mediated largely by its diverse input and output connections. It has also become clear that the LS is a heterogeneous region, where its dorsal and ventral poles play dissociable and often opposing roles. This functional heterogeneity can often be explained by distinct dorsal and ventral hippocampal inputs along the LS dorsoventral axis, as well as antagonizing connections between LS subregions. Similarly, outputs from LS subregions to respective downstream targets, such as hypothalamic, preoptic, and tegmental areas, also account for this functional heterogeneity. In this review, we provide an updated perspective on LS subregion classification, connectivity, and functio...

Excitatory amino acid transporters (EAATs) remove glutamate from the synaptic cleft. In the retina, EAAT1 and EAAT2 are considered the major glutamate transporters. However, it has not yet been possible to determine how EAAT5 shapes the retinal light responses because of the lack of a selective EAAT5 blocker or EAAT5 knock-out (KO) animal model. In this study, EAAT5 was found to be expressed in a punctate manner close to release sites of glutamatergic synapses in the mouse retina. Light responses from retinae of wild-type (WT) and of a newly generated model with a targeted deletion of EAAT5 (EAAT5−/−) were recorded in vitro using multielectrode arrays (MEAs). Flicker resolution was considerably lower in EAAT5−/− retinae than in WT retinae. The close proximity to the glutamate release site makes EAAT5 an ideal tool to improve temporal information processing in the retina by controlling information transfer at glutamatergic synapses.

Tracking and quantifying the abundance and location of cells in the developing brain is essential in neuroscience research, enabling a greater understanding of mechanisms underlying nervous system morphogenesis. Widely used experimental methods to quantify cells labeled with fluorescent markers, such as immunohistochemistry (IHC), in situ hybridization, and expression of transgenes via stable lines or transient in utero electroporations (IUEs), depend on accurate and consistent quantification of images. Current methods to quantify fluorescently-labeled cells rely on labor-intensive manual counting approaches, such as the Fiji plugin Cell Counter , which requires custom macros to enable higher-throughput analyses. Here, we present RapID Cell Counter, a semi-automated cell-counting tool with an easy-to-implement graphical user interface (GUI), which facilitates quick and consistent quantifications of cell density within user-defined boundaries that can be divided into equally-partitioned segments. Compared w...

Safe and efficient locomotion relies on placing the foot on a reliable surface at the end of each leg swing movement. Visual information has been shown to be important for determining the location of foot placement in humans during walking when precision is required. Yet in quadrupedal animals where the hindlimbs are outside of the visual field, such as in mice, the mechanisms by which precise foot placement is achieved remain unclear. Here we show that the placement of the hindlimb paw is determined by the position of the forelimb paw during normal locomotion and in the presence of perturbations. When a perturbation elicits a stumbling corrective reaction, we found that the forelimb paw shifts posteriorly relative to body at the end of stance, and this spatial shift is echoed in hindlimb paw placement at the end of the swing movement. Using a mutant mouse line in which muscle spindle feedback is selectively removed, we show that this posterior shift of paw placement is dependent on muscle spindle feedback...

Prosocial behavior is pivotal to our society. Guilt aversion, which describes the tendency to reduce the discrepancy between a partner’s expectation and his/her actual outcome, drives human prosocial behavior as does well-known inequity aversion. Although women are reported to be more inequity averse than men, gender differences in guilt aversion remain unexplored. Here, we conducted a functional magnetic resonance imaging (fMRI) study ( n  =   52) and a large-scale online behavioral study ( n  =   4723) of a trust game designed to investigate guilt and inequity aversions. The fMRI study demonstrated that men exhibited stronger guilt aversion and recruited right dorsolateral prefrontal cortex (DLPFC)-ventromedial PFC (VMPFC) connectivity more for guilt aversion than women, while VMPFC-dorsal medial PFC (DMPFC) connectivity was commonly used in both genders. Furthermore, our regression analysis of the online behavioral data collected with Big Five and demographic factors replicated the gender differences an...

Secreted amyloid-β (Aβ) peptide forms neurotoxic oligomeric assemblies thought to cause synaptic deficits associated with Alzheimer’s disease (AD). Soluble Aβ oligomers (Aβo) directly bind to neurons with high affinity and block plasticity mechanisms related to learning and memory, trigger loss of excitatory synapses and eventually cause cell death. While Aβo toxicity has been intensely investigated, it remains unclear precisely where Aβo initially binds to the surface of neurons and whether sites of binding relate to synaptic deficits. Here, we used a combination of live cell, super-resolution and ultrastructural imaging techniques to investigate the kinetics, reversibility and nanoscale location of Aβo binding. Surprisingly, Aβo does not bind directly at the synaptic cleft as previously thought but, instead, forms distinct nanoscale clusters encircling the postsynaptic membrane with a significant fraction also binding presynaptic axon terminals. Synaptic plasticity deficits were observed at Aβo-bound syn...

Sensorimotor circuits of the lumbosacral spinal cord are required for lower urinary tract (LUT) regulation as well as being engaged in pelvic pain states. To date, no molecular markers have been identified to enable specific visualization of LUT afferents, which are embedded within spinal cord segments that also subserve somatic functions. Moreover, previous studies have not fully investigated the patterning within or across spinal segments, compared afferent innervation of the bladder and urethra, or explored possible structural sex differences in these pathways. We have addressed these questions in adult Sprague Dawley rats, using intramural microinjection of the tract tracer, B subunit of cholera toxin (CTB). Afferent distribution was analyzed within individual sections and 3D reconstructions from sections across four spinal cord segments (L5-S2), and in cleared intact spinal cord viewed with light sheet microscopy. Simultaneous mapping of preganglionic neurons showed their location throughout S1 but re...

The activity-dependent expression of immediate-early genes (IEGs) has been utilized to label memory traces. However, their roles in engram specification are incompletely understood. Outstanding questions remain as to whether expression of IEGs can interplay with network properties such as functional connectivity and also if neurons expressing different IEGs are functionally distinct. In order to connect IEG expression at the cellular level with changes in functional connectivity, we investigated the expression of 2 IEGs, Arc and c-Fos, in cultured hippocampal neurons. Primary neuronal cultures were treated with a chemical cocktail [4-aminopyridine (4AP), bicuculline (Bic), and forskolin] to increase neuronal activity, IEG expression, and induce chemical long-term potentiation (LTP). Neuronal firing is assayed by intracellular calcium imaging using GCaMP6m and expression of IEGs is assessed by immunofluorescence staining. We noted an emergent network property of refinement in network activity, characterized...

Water restriction is commonly used to motivate rodents to perform behavioral tasks; however, its effects on hydration and stress hormone levels are unknown. Here, we report daily body weight and bi-weekly packed red blood cell volume and corticosterone (CORT) in adult male rats across 80 days for three commonly used water restriction schedules. We also assessed renal adaptation to water restriction using postmortem histologic evaluation of renal medulla. A control group received ad libitum water. After one week of water restriction, rats on all restriction schedules resumed similar levels of growth relative to the control group. Normal hydration was observed, and water restriction did not drive renal adaptation. An intermittent restriction schedule was associated with an increase in CORT relative to the control group. However, intermittent restriction evokes a stress response which could affect behavioral and neurobiological results. Our results also suggest that stable motivation in behavioral tasks may o...