Auditory stimuli travel from the cochlea to the brainstem through type I and type II cochlear afferents. While type I afferents convey information about the frequency, intensity, and timing of sounds, the role of type II afferents remains unresolved. Limited recordings of type II afferents from cochlear apex of prehearing rats reveal they are activated by widespread outer hair cell stimulation, ATP, and by the rupture of nearby outer hair cells. Altogether, these lines of evidence suggest that type II afferents sense loud, potentially damaging levels of sound. To explore this hypothesis further, calcium imaging was used to determine the impact of acoustic trauma on the activity of type II cochlear afferents of young adult mice of both sexes. Two known marker genes ( Th , Drd2 ) and one new marker gene ( Tac1 ), expressed in type II afferents and some other cochlear cell types, drove GCaMP6f expression to reveal calcium transients in response to focal damage in the organ of Corti in all turns of the cochlea...

Human heading perception from optic flow is accurate for directions close to the straight-ahead and systematic biases emerge in the periphery ([Cuturi and Macneilage, 2013][1]; [Sun et al., 2020][2]). In pursuit of the underlying neural mechanisms, primate brain dorsal medial superior temporal (MSTd) area has been a focus because of its causal link with heading perception ([Gu et al., 2012][3]). Computational models generally explain heading sensitivity in individual MSTd neurons as a feedforward integration of motion signals from medial temporal (MT) area that resemble full-field optic flow patterns consistent with the preferred heading direction ([Britten, 2008][4]; [Mineault et al., 2012][5]). In the present simulation study, we quantified within the structure of this feedforward model how physiological properties of MT and MSTd shape heading signals. We found that known physiological tuning characteristics generally supported the accuracy of heading estimation, but not always. A weak-to-moderate overre...

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...

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...

Forced swim test (FST) and tail suspension test (TST) are commonly used behavioral tests for screening antidepressant drugs with a high predictive validity. These tests have also proved useful to assess the non-motor symptoms in the animal models of movement disorders such as Parkinson’s disease and Huntington’s disease. Manual analysis of FST and TST is a time-consuming exercise and has large observer-to-observer variability. Automation of behavioral analysis alleviates these concerns, but there are no easy-to-use open-source tools for such analysis. Here, we describe the development of Depression Behavior Scorer (DBscorer), an open-source program installable on Windows, with an intuitive graphical user interface (GUI), that helps in accurate quantification of immobility behavior in FST and TST from video analysis. Several calibration options allow customization of various parameters to suit the experimental requirements. Apart from the readout of time spent immobile, DBscorer also provides additional dat...

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...

Inflammatory cells including macrophages and microglia synthesize and release the oxysterol, 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild type microglia produced higher levels of 25HC than Ch25h knockout (KO) microglial with or without LPS. LPS treatment also disrupts long-term potentiation (LTP) in hippocampal slices via induction of a form of NMDA receptor-dependent metaplasticity. The inhibitory effects of LPS on LTP were mimicked by exogenous 25HC, and were not observed in slices from Ch25h KO mice. In vivo, LPS treatment also disrupts LTP and inhibits one-trial learning in wi...

Numerous brain regions have been identified as contributing to withdrawal behaviors, but it is unclear the way in which these brain regions as a whole lead to withdrawal. The search for a final common brain pathway that is involved in withdrawal remains elusive. To address this question, we implanted osmotic minipumps containing either saline, nicotine (24 mg/kg/d), cocaine (60 mg/kg/d), or methamphetamine (4 mg/kg/d) for one week in male C57BL/6J mice. After one week, the minipumps were removed and brains collected 8 h (saline, nicotine, and cocaine) or 12 h (methamphetamine) after removal. We then performed single-cell whole-brain imaging of neural activity during the withdrawal period when brains were collected. We used hierarchical clustering and graph theory to identify similarities and differences in brain functional architecture. Although methamphetamine and cocaine shared some network similarities, the main common neuroadaptation between these psychostimulant drugs was a dramatic decrease in modula...

The hippocampus and amygdala are functionally coupled brain regions that play a crucial role in processes involving memory and learning. Because interareal communication has been reported both during specific sleep stages and in awake, behaving animals, these brain regions can serve as an archetype to establish that measuring functional interactions is important for comprehending neural systems. To this end, we analyze here a public dataset of local field potentials (LFPs) recorded in rats simultaneously from the hippocampus and amygdala during different behaviors. Employing a specific, time-lagged embedding technique, named topological causality (TC), we infer directed interactions between the LFP band powers of the two regions across six frequency bands in a time-resolved manner. The combined power and interaction signals are processed with our own unsupervised tools developed originally for the analysis of molecular dynamics simulations to effectively visualize and identify putative, neural states that ...

Sensory environments are commonly characterized by specific physical features, which sensory systems might exploit using dedicated processing mechanisms. In the tactile sense, one such characteristic feature is frictional movement, which gives rise to short-lasting (<10 ms), information-carrying integument vibrations. Rather than generic integrative encoding (i.e., averaging or spectral analysis capturing the “intensity” and “best frequency”), the tactile system might benefit from, what we call a “temporally local” coding scheme that instantaneously detects and analyzes shapes of these short-lasting features. Here, by employing analytic psychophysical measurements, we tested whether the prerequisite of temporally local coding exists in the human tactile system. We employed pulsatile skin indentations at the fingertip that allowed us to trade manipulation of local pulse shape against changes in global intensity and frequency, achieved by adding pulses of the same shape. We found that manipulation of local p...