Dynamic synchronization between hippocampal representations and stepping.

The hippocampus is a mammalian brain structure that expresses spatial representations1 and is crucial for navigation2,3. Navigation, in turn, intricately depends on locomotion; however, current accounts suggest a dissociation between hippocampal spatial representations and the details of locomotor processes. Specifically, the hippocampus is thought to represent mainly higher-order cognitive and locomotor variables such as position, speed and direction of movement4-7, whereas the limb movements that propel the animal can be computed and represented primarily in subcortical circuits, including the spinal cord, brainstem and cerebellum8-11. Whether hippocampal representations are actually decoupled from the detailed structure of locomotor processes remains unknown. To address this question, here we simultaneously monitored hippocampal spatial representations and ongoing limb movements underlying locomotion at fast timescales. We found that the forelimb stepping cycle in freely behaving rats is rhythmic and peaks at around 8 Hz during movement, matching the approximately 8 Hz modulation of hippocampal activity and spatial representations during locomotion12. We also discovered precisely timed coordination between the time at which the forelimbs touch the ground ('plant' times of the stepping cycle) and the hippocampal representation of space. Notably, plant times coincide with hippocampal representations that are closest to the actual position of the nose of the rat, whereas between these plant times, the hippocampal representation progresses towards possible future locations. This synchronization was specifically detectable when rats approached spatial decisions. Together, our results reveal a profound and dynamic coordination on a timescale of tens of milliseconds between central cognitive representations and peripheral motor processes. This coordination engages and disengages rapidly in association with cognitive demands and is well suited to support rapid information exchange between cognitive and sensory-motor circuits.

Interdisciplinary views of fNIRS: Current advancements, equity challenges, and an agenda for future needs of a diverse fNIRS research community.

Functional Near-Infrared Spectroscopy (fNIRS) is an innovative and promising neuroimaging modality for studying brain activity in real-world environments. While fNIRS has seen rapid advancements in hardware, software, and research applications since its emergence nearly 30 years ago, limitations still exist regarding all three areas, where existing practices contribute to greater bias within the neuroscience research community. We spotlight fNIRS through the lens of different end-application users, including the unique perspective of a fNIRS manufacturer, and report the challenges of using this technology across several research disciplines and populations. Through the review of different research domains where fNIRS is utilized, we identify and address the presence of bias, specifically due to the restraints of current fNIRS technology, limited diversity among sample populations, and the societal prejudice that infiltrates today's research. Finally, we provide resources for minimizing bias in neuroscience research and an application agenda for the future use of fNIRS that is equitable, diverse, and inclusive.

Spatial preferences account for inter-animal variability during the continual learning of a dynamic cognitive task.

Understanding the complexities of behavior is necessary to interpret neurophysiological data and establish animal models of neuropsychiatric disease. This understanding requires knowledge of the underlying information-processing structure-something often hidden from direct observation. Commonly, one assumes that behavior is solely governed by the experimenter-controlled rules that determine tasks. For example, differences in tasks that require memory of past actions are often interpreted as exclusively resulting from differences in memory. However, such assumptions are seldom tested. Here, we provide a comprehensive examination of multiple processes that contribute to behavior in a prevalent experimental paradigm. Using a combination of behavioral automation, hypothesis-driven trial design, and reinforcement learning modeling, we show that rats learn a spatial alternation task consistent with their drawing upon spatial preferences in addition to memory. Our approach also distinguishes learning based on established preferences from generalization of task structure, providing further insights into learning dynamics.

Hippocampal replay reflects specific past experiences rather than a plan for subsequent choice.

Executing memory-guided behavior requires storage of information about experience and later recall of that information to inform choices. Awake hippocampal replay, when hippocampal neural ensembles briefly reactivate a representation related to prior experience, has been proposed to critically contribute to these memory-related processes. However, it remains unclear whether awake replay contributes to memory function by promoting the storage of past experiences, facilitating planning based on evaluation of those experiences, or both. We designed a dynamic spatial task that promotes replay before a memory-based choice and assessed how the content of replay related to past and future behavior. We found that replay content was decoupled from subsequent choice and instead was enriched for representations of previously rewarded locations and places that had not been visited recently, indicating a role in memory storage rather than in directly guiding subsequent behavior.

Chronic Implantation of Multiple Flexible Polymer Electrode Arrays.

Simultaneous recordings from large populations of individual neurons across distributed brain regions over months to years will enable new avenues of scientific and clinical development. The use of flexible polymer electrode arrays can support long-lasting recording, but the same mechanical properties that allow for longevity of recording make multiple insertions and integration into a chronic implant a challenge. Here is a methodology by which multiple polymer electrode arrays can be targeted to a relatively spatially unconstrained set of brain areas. The method utilizes thin-film polymer devices, selected for their biocompatibility and capability to achieve long-term and stable electrophysiologic recording interfaces. The resultant implant allows accurate and flexible targeting of anatomically distant regions, physical stability for months, and robustness to electrical noise. The methodology supports up to sixteen serially inserted devices across eight different anatomic targets. As previously demonstrated, the methodology is capable of recording from 1024 channels. Of these, the 512 channels in this demonstration used for single neuron recording yielded 375 single units distributed across six recording sites. Importantly, this method also can record single units for at least 160 days. This implantation strategy, including temporarily bracing each device with a retractable silicon insertion shuttle, involves tethering of devices at their target depths to a skull-adhered plastic base piece that is custom-designed for each set of recording targets, and stabilization/protection of the devices within a silicone-filled, custom-designed plastic case. Also covered is the preparation of devices for implantation, and design principles that should guide adaptation to different combinations of brain areas or array designs.

A microfabricated, 3D-sharpened silicon shuttle for insertion of flexible electrode arrays through dura mater into brain.

OBJECTIVE: Electrode arrays for chronic implantation in the brain are a critical technology in both neuroscience and medicine. Recently, flexible, thin-film polymer electrode arrays have shown promise in facilitating stable, single-unit recordings spanning months in rats. While array flexibility enhances integration with neural tissue, it also requires removal of the dura mater, the tough membrane surrounding the brain, and temporary bracing to penetrate the brain parenchyma. Durotomy increases brain swelling, vascular damage, and surgical time. Insertion using a bracing shuttle results in additional vascular damage and brain compression, which increase with device diameter; while a higher-diameter shuttle will have a higher critical load and more likely penetrate dura, it will damage more brain parenchyma and vasculature. One way to penetrate the intact dura and limit tissue compression without increasing shuttle diameter is to reduce the force required for insertion by sharpening the shuttle tip. APPROACH: We describe a novel design and fabrication process to create silicon insertion shuttles that are sharp in three dimensions and can penetrate rat dura, for faster, easier, and less damaging implantation of polymer arrays. Sharpened profiles are obtained by reflowing patterned photoresist, then transferring its sloped profile to silicon with dry etches. MAIN RESULTS: We demonstrate that sharpened shuttles can reliably implant polymer probes through dura to yield high quality single unit and local field potential recordings for at least 95 days. On insertion directly through dura, tissue compression is minimal. SIGNIFICANCE: This is the first demonstration of a rat dural-penetrating array for chronic recording. This device obviates the need for a durotomy, reducing surgical time and risk of damage to the blood-brain barrier. This is an improvement to state-of-the-art flexible polymer electrode arrays that facilitates their implantation, particularly in multi-site recording experiments. This sharpening process can also be integrated into silicon electrode array fabrication.

Coordinated Excitation and Inhibition of Prefrontal Ensembles during Awake Hippocampal Sharp-Wave Ripple Events.

Interactions between the hippocampus and prefrontal cortex (PFC) are critical for learning and memory. Hippocampal activity during awake sharp-wave ripple (SWR) events is important for spatial learning, and hippocampal SWR activity often represents past or potential future experiences. Whether or how this reactivation engages the PFC, and how reactivation might interact with ongoing patterns of PFC activity, remains unclear. We recorded hippocampal CA1 and PFC activity in animals learning spatial tasks and found that many PFC cells showed spiking modulation during SWRs. Unlike in CA1, SWR-related activity in PFC comprised both excitation and inhibition of distinct populations. Within individual SWRs, excitation activated PFC cells with representations related to the concurrently reactivated hippocampal representation, while inhibition suppressed PFC cells with unrelated representations. Thus, awake SWRs mark times of strong coordination between hippocampus and PFC that reflects structured reactivation of representations related to ongoing experience.

Hippocampal sharp-wave ripples in waking and sleeping states.

Waking and sleeping states are privileged periods for distinct mnemonic processes. In waking behavior, rapid retrieval of previous experience aids memory-guided decision making. In sleep, a gradual series of reactivated associations supports consolidation of episodes into memory networks. Synchronized bursts of hippocampal place cells during events called sharp-wave ripples communicate associated neural patterns across distributed circuits in both waking and sleeping states. Differences between sleep and awake sharp-wave ripples, and in particular the accuracy of recapitulated experience, highlight their state-dependent roles in memory processes.

Removable cranial windows for long-term imaging in awake mice.

Cranial window implants in head-fixed rodents are becoming a preparation of choice for stable optical access to large areas of the cortex over extended periods of time. Here we provide a highly detailed and reliable surgical protocol for a cranial window implantation procedure for chronic wide-field and cellular imaging in awake, head-fixed mice, which enables subsequent window removal and replacement in the weeks and months after the initial craniotomy. This protocol has facilitated awake, chronic imaging in adolescent and adult mice over several months from a large number of cortical brain regions; targeted virus and tracer injections from data obtained using prior awake functional mapping; and functionally targeted two-photon imaging across all cortical layers in awake mice using a microprism attachment to the cranial window. Collectively, these procedures extend the reach of chronic imaging of cortical function and dysfunction in behaving animals.

Synaptic plasticity defect following visual deprivation in Alzheimer's disease model transgenic mice.

Amyloid-ß (Aß)-induced changes in synaptic function in experimental models of Alzheimer's disease (AD) suggest that Aß generation and accumulation may affect fundamental mechanisms of synaptic plasticity. To test this hypothesis, we examined the effect of APP overexpression on a well characterized, in vivo, developmental model of systems-level plasticity, ocular dominance plasticity. Following monocular visual deprivation during the critical period, mice that express mutant alleles of amyloid precursor protein (APPswe) and Presenilin1 (PS1dE9), as well as mice that express APPswe alone, lack ocular dominance plasticity in visual cortex. Defects in the spatial extent and magnitude of the plastic response are evident using two complementary approaches, Arc induction and optical imaging of intrinsic signals in awake mice. This defect in a classic paradigm of systems level synaptic plasticity shows that Aß overexpression, even early in postnatal life, can perturb plasticity in cerebral cortex, and supports the idea that decreased synaptic plasticity due to elevated Aß exposure contributes to cognitive impairment in AD.

Functional specialization of mouse higher visual cortical areas.

The mouse is emerging as an important model for understanding how sensory neocortex extracts cues to guide behavior, yet little is known about how these cues are processed beyond primary cortical areas. Here, we used two-photon calcium imaging in awake mice to compare visual responses in primary visual cortex (V1) and in two downstream target areas, AL and PM. Neighboring V1 neurons had diverse stimulus preferences spanning five octaves in spatial and temporal frequency. By contrast, AL and PM neurons responded best to distinct ranges of stimulus parameters. Most strikingly, AL neurons preferred fast-moving stimuli while PM neurons preferred slow-moving stimuli. By contrast, neurons in V1, AL, and PM demonstrated similar selectivity for stimulus orientation but not for stimulus direction. Based on these findings, we predict that area AL helps guide behaviors involving fast-moving stimuli (e.g., optic flow), while area PM helps guide behaviors involving slow-moving objects.