Biology subjects

Snyder, J. S.

Publications and source records attributed to Snyder, J. S..

At least 19 recordsLinked to original sources

bioRxiv2026

NC4touch: An open-source networked touchscreen apparatus for rodent behavioral testing

In recent years, rodent touchscreen-based paradigms have gained popularity for their flexible task design, automated data collection and improved standardization. These devices minimize experimenter intervention and contribute to more replicable and reliable research. However, the high costs and proprietary hardware / software associated with commercially available systems present a financial barrier for smaller labs or researchers with limited resources. To address this issue, we developed "NC4Touch", an open-source scalable, modular rodent testing apparatus. It features three independent touchscreens and a feeding port for easy use in a wide array of tests comparable to those available with standard operant chambers, with the added benefit that visual stimuli can be highly customized. The system includes a user-friendly graphical interface that offers real-time control, task customization, video recording, and data management. We demonstrate its effectiveness in a visual discrimination task using both rats and mice. Several devices can be operated in parallel from the same computer and user interface, allowing high- throughput data collection. We provide detailed assembly instructions for the hardware and well- documented and easily-configurable software. We hope that the affordable open-source nature of NC4Touch will expand the scope of behavioral testing, allowing researchers to overcome traditional financial barriers and create a more collaborative community. Significance StatementTouchscreen-based testing is a powerful tool for assessing cognition in rodent models, however commercial systems remain cost-prohibitive for many researchers. NC4Touch is a rodent touchscreen apparatus that provides an open-source, customizable, and affordable alternative that enables high-throughput, cognitive testing in both mice and rats. By lowering financial barriers and promoting hackability, this system enables greater accessibility and collaboration in research.

animal behavior and cognition↗

bioRxiv2026

The dentate gyrus grows throughout life despite turnover of developmentally-born neurons

Adult-born hippocampal neurons are highly plastic but there remains uncertainty about the magnitude of neurogenesis and its long-term functional consequences. Theoretical predictions indicate that adult neurogenesis should lead to substantial growth of the dentate gyrus (DG) granule cell population. However, in practice, most studies find no changes in total cell number across adulthood. This discrepancy may partly be a sensitivity issue, where small sample sizes and the examination of older age windows (when neurogenesis is reduced) have prevented detection. However, neurogenic growth could also be masked by the turnover of developmentally-born DG neurons, which are known to die off in normal aging. To address the question of how neuronal birth and loss impacts DG population dynamics, here we quantified numbers of developmentally-born neurons, proliferating Ki67+ cells (as a proxy for adult-born neurons), and total DG neurons from 2-18 months of age in the rat. We estimate that over this timeframe 670,000 adult-born neurons are added (30% of the total population). Consistent with neurogenic growth, the total number of DG neurons increased across adulthood. However, net growth was only 385,000 cells, which is less than predicted by adult neurogenesis alone. Indeed, 20% of developmentally-born neurons were lost over the same interval, and so we propose that the difference is explained by neuronal turnover. Neuronal persistence and turnover may be relevant for theories of hippocampal long-term memory, as well as for understanding psychiatric conditions that are characterized by hippocampal plasticity and atrophy.

neuroscience↗

bioRxiv2025

Chronic electroconvulsive shock disrupts hippocampal physiology and impairs associative memory in mice

Electroconvulsive therapy (ECT) is a highly effective treatment for depression but it has undesirable side effects on various aspects of cognition, including memory. Patients might display retrograde amnesia for autobiographical events and anterograde amnesia in tests of recall and recognition memory. These amnestic effects are likely to depend, at least in part, on changes in the hippocampus. ECT-induced volume increases in the hippocampus, and dentate gyrus subregion in particular, correlate with the cognitive deficits. However, the precise cellular and behavioral effects of ECT remain poorly understood. Here, we therefore subjected male and female mice to chronic electroconvulsive shock (ECS) and examined effects on hippocampal physiology and memory. Perforant path inputs onto dentate gyrus neurons were examined using whole cell patch clamp recordings in hippocampal slices. In the intact slice, perforant path stimulation did not result in any synaptic or spiking differences in mice given sham vs ECS treatments. However, GABAA blockade increased depolarization and spiking in sham, but not ECS-treated, mice. Voltage clamp recordings further revealed weaker perforant path excitation of dentate gyrus neurons in ECS-treated mice. Extrapolating these findings to the intact animal, we then used Fos expression as a proxy for neural activity, and found that ECS blunted exploration-induced hippocampal activation, which was most pronounced in the dentate gyrus. Finally, recognition memory tasks revealed that ECS impaired memory for object-context associations but not memory for objects or locations. Collectively, these experiments reveal that a clinically relevant schedule of ECS disrupts synaptic and circuit functions of the hippocampus and causes anterograde amnesia in a test of episodic-like associative memory.

neuroscience↗

bioRxiv2025

A mouse model of early sporadic tau pathology induces neurogenic plasticity in the hippocampus

Alzheimers disease is characterized by widespread neurodegeneration and the accumulation of insoluble amyloid plaques and neurofibrillary tangles. However, at the earliest stages of the disease cell death and pathological tau are localized to the entorhinal cortex. In particular, the lateral entorhinal cortex, and its functions in object-related memory, are among the most vulnerable in aging. Notably, the entorhinal cortex projects directly to the dentate gyrus subregion of the hippocampus, where neurogenesis proceeds throughout adult life. Immature, adult-born neurons provide a robust source of plasticity to the entorhinal-dentate pathway and they may be uniquely responsive, or vulnerable, to early entorhinal tau pathology. To test this, we injected a human tau-expressing recombinant adeno-associated virus into the lateral entorhinal cortex and used AsclCreER mice to birthdate downstream dentate neurons born in early postnatal development or adulthood. Consistent with known roles in neurodegeneration, lateral entorhinal tau expression caused a loss of mushroom spines in downstream dentate neurons and reduced dendritic complexity of adult-born neurons in male mice. Presynaptic tau also increased neurogenesis levels and increased the density of thin spines on adult-born neurons. Despite these morphological effects, tau did not alter synaptic strength or the magnitude of long-term potentiation at entorhinal synapses onto adult- or developmentally-born neurons. Thus, in a novel model of early sporadic tau pathology, there are morphological changes consistent with neurodegeneration but also compensatory neuroplastic changes, caused by neurogenesis. Since immature neurons have also been identified in the human dentate gyrus, a similar neurogenic plasticity may help maintain entorhinal-hippocampal formation in pathological aging.

neuroscience↗

bioRxiv2025

Registered Report: Replication and Extension of Nozaradan, Peretz, Missal and Mouraux (2011)

Cognitive neuroscience has long sought to disentangle stimulus-driven processing from conscious perceptual processing. Some prior evidence for neural processing of perceived musical beat (periodic pulse) may be confounded by stimulus-driven activity. Notably, Nozaradan et al. (2011) controlled for stimulus factors and used frequency tagging to show increased brain activity at imagery-related frequencies when listeners imagined a beat pattern during an isochronous stimulus. However, it remains unclear whether this effect is replicable and whether it reliably reflects conscious beat perception. This registered report presents 13 independent replications using the same vetted protocol. Listeners performed the same experimental paradigm as in Nozaradan et al. (2011), with an added behavioral task on each trial to assess conscious perception of the imagined beat. Pre-registered meta-analyses revealed smaller raw effect sizes of imagery condition (Binary: 0.03 {micro}V, Ternary: 0.03 {micro}V) than the original study (Binary: 0.12 {micro}V, Ternary: 0.20 {micro}V), with confidence intervals all overlapping with 0. Differences in full-sample estimated effect sizes (this study: n = 152, p2 = .03-.04; 2011 study: n = 8, p2 = .62- .76) suggest larger sample sizes are necessary to detect these effects reliably, if they exist. Additionally, only neural activity at the stimulus frequency predicted imagery task accuracy, contradicting our hypothesis that beat-related frequencies would predict performance. Our findings suggest an overall failure to replicate all main effects from the original study. We discuss potential reasons for discrepancies with the original study as well as implications for the utility of frequency tagging for studying beat perception.

neuroscience↗

bioRxiv2023

Neurogenesis-mediated circuit remodeling reduces engram reinstatement and promotes forgetting

Post-training increases in hippocampal neurogenesis are associated with forgetting of hippocampus-dependent memories in adult mice. This form of forgetting might be due to increased numbers of new neurons, remodeling of hippocampal circuitry or some combination of both. Here we tested the hypothesis that neurogenesis-mediated forgetting is caused by remodeling of hippocampal circuits by engineering mice in which adult-generated granule cells hypo- or hyper-integrate into hippocampal circuits. Using gene deletion, opto- and chemogenetic strategies, we find that hypo-integration of newborn neurons prevents post- training exercise-induced forgetting of contextual fear memories. Conversely, inducing hyper- integration of newborn neurons following contextual fear conditioning is sufficient to produce forgetting. Because these interventions did not affect survival of newborn neurons, these findings suggest that neurogenesis-mediated remodeling of hippocampal circuits represents a continuous and active form of interference that alters accessibility of engrams underlying hippocampal memories. Consistent with this, using engram-labeling approaches, we found that exercise-induced forgetting was associated with reduced engram reactivation.

neuroscience↗

bioRxiv2021

Inhibiting adult neurogenesis differentially affects spatial learning in females and males

Adult hippocampal neurogenesis has been implicated in the spatial processing functions of the hippocampus but ablating neurogenesis does not consistently lead to behavioral deficits in spatial tasks. Parallel studies have shown that adult-born neurons also regulate behavioral responses to stressful and aversive stimuli. We therefore hypothesized that spatial functions of adult-born neurons may be more prominent under conditions of stress, and may differ between males and females given established sex differences in stress responding. To test this we trained intact and neurogenesis-deficient rats in the spatial water maze at temperatures that vary in their degree of aversiveness. At standard temperatures (25{degrees}C) ablating neurogenesis did not alter learning and memory in either sex, consistent with prior work. However, in cold water (16{degrees}C), ablating neurogenesis had divergent sex-dependent effects: relative to intact rats, male neurogenesis-deficient rats were slower to escape and female neurogenesis-deficient rats were faster. Neurogenesis promoted temperature-related changes in search strategy in females, but it promoted search strategy stability in males. Females displayed greater recruitment of the dorsal hippocampus than males, particularly at 16{degrees}C. However, blocking neurogenesis did not alter activity-dependent immediate-early gene expression in either sex. Finally, morphological analyses of retrovirally-labelled neurons revealed greater experience-dependent plasticity in new neurons in males. Neurons had comparable morphology in untrained rats but 16{degrees}C training increased spine density, and 25{degrees}C training caused shrinkage of mossy fiber presynaptic terminals, specifically in males. Collectively, these findings indicate that neurogenesis functions in memory are prominent under conditions of stress, they provide the first evidence for sex differences in the behavioral function of newborn neurons, and they suggest possibly distinct roles for neurogenesis in cognition and mental health in males and females.

neuroscience↗

bioRxiv2021

Prolonged development of long-term potentiation at lateral entorhinal cortex synapses onto adult-born neurons

Critical period plasticity at adult-born neuron synapses is widely believed to contribute to the learning and memory functions of the hippocampus. Experience regulates circuit integration and for a transient interval, until cells are ~6 weeks old, new neurons display enhanced long-term potentiation (LTP) at afferent and efferent synapses. Since neurogenesis declines substantially with age, this raises questions about the extent of lasting plasticity offered by adult-born neurons. Notably, however, the hippocampus receives sensory information from two major cortical pathways. Broadly speaking, the medial entorhinal cortex conveys spatial information to the hippocampus via the medial perforant path (MPP), and the lateral entorhinal cortex, via the lateral perforant path (LPP), codes for the cues and items that make experiences unique. While enhanced critical period plasticity at MPP synapses is relatively well characterized, no studies have examined long-term plasticity at LPP synapses onto adult-born neurons, even though the lateral entorhinal cortex is uniquely vulnerable to aging and Alzheimers pathology. We therefore investigated LTP at LPP inputs both within (4-6 weeks) and beyond (8+ weeks) the traditional critical period. At immature stages, adult-born neurons did not undergo significant LTP at LPP synapses, and often displayed long-term depression after theta burst stimulation. However, over the course of 3-4 months, adult-born neurons displayed increasingly greater amounts of LTP. Analyses of short-term plasticity point towards a presynaptic mechanism, where transmitter release probability declines as cells mature, providing a greater dynamic range for strengthening synapses. Collectively, our findings identify a novel form of new neuron plasticity that develops over an extended interval, and may therefore be relevant for maintaining cognitive function in aging.

neuroscience↗

bioRxiv2021

Going beyond rote auditory learning: Neural patterns of generalized auditory learning

The ability to generalize rapidly across specific experiences is vital for robust recognition of new patterns, especially in speech perception considering acoustic-phonetic pattern variability. Behavioral research has demonstrated that listeners are rapidly able to generalize their experience with a talkers speech and quickly improve understanding of a difficult-to-understand talker without prolonged practice, e.g., even after a single training session. Here, we examine the differences in neural responses to generalized versus rote learning in auditory cortical processing by training listeners to understand a novel synthetic talker using a Pretest-Posttest design with electroencephalography (EEG). Participants were trained using either (1) a large inventory of words where no words repeated across the experiment (generalized learning) or (2) a small inventory of words where words repeated (rote learning). Analysis of long-latency auditory evoked potentials at Pretest and Posttest revealed that while rote and generalized learning both produce rapid changes in auditory processing, the nature of these changes differed. In the context of adapting to a talker, generalized learning is marked by an amplitude reduction in the N1-P2 complex and by the presence of a late-negative (LN) wave in the auditory evoked potential following training. Rote learning, however, is marked only by temporally later source configuration changes. The early N1-P2 change, found only for generalized learning, suggests that generalized learning relies on the attentional system to reorganize the way acoustic features are selectively processed. This change in relatively early sensory processing (i.e. during the first 250ms) is consistent with an active processing account of speech perception, which proposes that the ability to rapidly adjust to the specific vocal characteristics of a new talker (for which rote learning is rare) relies on attentional mechanisms to adaptively tune early auditory processing sensitivity. Statement of SignificancePrevious research on perceptual learning has typically examined neural responses during rote learning: training and testing is carried out with the same stimuli. As a result, it is not clear that findings from these studies can explain learning that generalizes to novel patterns, which is critical in speech perception. Are neural responses to generalized learning in auditory processing different from neural responses to rote learning? Results indicate rote learning of a particular talkers speech involves brain regions focused on the memory encoding and retrieving of specific learned patterns, whereas generalized learning involves brain regions involved in reorganizing attention during early sensory processing. In learning speech from a novel talker, only generalized learning is marked by changes in the N1-P2 complex (reflective of secondary auditory cortical processing). The results are consistent with the view that robust speech perception relies on the fast adjustment of attention mechanisms to adaptively tune auditory sensitivity to cope with acoustic variability.

neuroscience↗

bioRxiv2019

Adult-born hippocampal neurons undergo extended development and are morphologically distinct from neonatally-born neurons

During immature stages, adult-born neurons pass through critical periods for survival and plasticity. It is generally assumed that by 2 months of age adult-born neurons are mature and equivalent to the broader neuronal population, raising questions of how they might contribute to hippocampal function in old age when neurogenesis has declined. However, few have examined adult-born neurons beyond the critical period, or directly compared them to neurons born in infancy. Here, we used a retrovirus to visualize functionally-relevant morphological features of 2- to 24-week-old adult-born neurons in male rats. From 2-7 weeks neurons grew and attained a relatively mature phenotype. However, several features of 7-week-old neurons suggested a later wave of growth: these neurons had larger nuclei, thicker dendrites and more dendritic filopodia than all other groups. Indeed, between 7-24 weeks, adult-born neurons gained additional dendritic branches, grew a 2nd primary dendrite, acquired more mushroom spines and had enlarged mossy fiber presynaptic terminals. Compared to neonatally-born neurons, old adult-born neurons had greater spine density, larger presynaptic terminals, and more putative efferent filopodial contacts onto inhibitory neurons. By integrating rates of cell birth and growth across the lifespan, we estimate that adult neurogenesis ultimately produces half of the cells and the majority of spines in the dentate gyrus. Critically, protracted development contributes to the plasticity of the hippocampus through to the end of life, even after cell production declines. Persistent differences from neonatally-born neurons may additionally endow adult-born neurons with unique functions even after they have matured. SIGNIFICANCE STATEMENTNeurogenesis occurs in the hippocampus throughout adult life and contributes to memory and emotion. It is generally assumed that new neurons have the greatest impact on behavior when they are immature and plastic. However, since neurogenesis declines dramatically with age, it is unclear how they might contribute to behavior later in life when cell proliferation has slowed. Here we find that newborn neurons mature over many months in rats, and end up with distinct morphological features compared to neurons born in infancy. Using a mathematical model, we estimate that a large fraction of neurons is added in adulthood. Moreover, their extended growth produces a reserve of plasticity that persists even after neurogenesis has declined to low rates.

neuroscience↗

bioRxiv2019

Neural correlates of perceptual switching while listening to bistable auditory streaming stimuli

Understanding the neural underpinning of conscious perception remains one of the primary challenges of cognitive neuroscience. Theories based mostly on studies of the visual system differ according to whether the neural activity giving rise to conscious perception occurs in modality-specific sensory cortex or in associative areas, such as the frontal and parietal cortices. Here, we search for modality-specific conscious processing in the auditory cortex using a bistable stream segregation paradigm that presents a constant stimulus without the confounding influence of physical changes to sound properties. ABA_ triplets (i.e., alternating low, A, and high, B, tones, and _ gap) with a 700 ms silent response period after every third triplet were presented repeatedly, and human participants reported nearly equivalent proportions of 1- and 2-stream percepts. The pattern of behavioral responses was consistent with previous studies of visual and auditory bistable perception. The intermittent response paradigm has the benefit of evoking spontaneous perceptual switches that can be attributed to a well-defined stimulus event, enabling precise identification of the timing of perception-related neural events with event-related potentials (ERPs). Significantly more negative ERPs were observed for 2-streams compared to 1-stream, and for switches compared to non-switches during the sustained potential (500-1000 ms post-stimulus onset). Further analyses revealed that the negativity associated with switching was independent of switch direction, suggesting that spontaneous changes in perception have a unique neural signature separate from the observation that 2-streams has more negative ERPs than 1-stream. Source analysis of the sustained potential showed activity associated with these differences originating in anterior superior temporal gyrus, indicating involvement of the ventral auditory pathway that is important for processing auditory objects.\n\nSignificance StatementWhen presented with ambiguous stimuli, the auditory system takes the available information and attempts to construct a useful percept. When multiple percepts are possible from the same stimuli, however, perception fluctuates back and forth between alternating percepts in a bistable manner. Here, we examine spontaneous switches in perception using a bistable auditory streaming paradigm with a novel intermittent stimulus paradigm, and measure sustained electrical activity in anterior portions of auditory cortex using event-related potentials. Analyses revealed enhanced sustained cortical activity when perceiving 2-streams compared to 1-stream, and when a switch occurred regardless of switch direction. These results indicate that neural responses in auditory cortex reflect both the content of perception and neural dynamics related to switches in perception.

neuroscience↗

bioRxiv2019

Dentate gyrus neurons that are born at the peak of development, but not before or after, die in adulthood

In the dentate gyrus of the rodent hippocampus, neurogenesis begins prenatally and continues to the end of life. Adult-born neurons often die in the first few weeks after mitosis, but then survive indefinitely. In contrast, neurons born at the peak of development are initially stable but can die later in adulthood. Physiological and pathological changes in hippocampal structure may therefore result from both the addition of new neurons and the loss of older neurons. However, it is unknown whether neurons born at other stages of development also undergo delayed cell death. Here, we used BrdU to label dentate granule cells that were born in rats on embryonic day 19 (E19; before the developmental peak), postnatal day 6 (P6; peak) and P21 (after the peak). We quantified BrdU+ neurons in separate groups of rats at 2 and 6 months post-BrdU injection. Consistent with previous work, there was a 15% loss of P6-born neurons between 2 and 6 months of age. In contrast, E19- or P21-born neurons were stable throughout young adulthood. Delayed death of P6-born neurons suggests they may play a unique role in hippocampal plasticity and pathology in adulthood.

neuroscience↗

bioRxiv2019

Ensemble modeling of auditory streaming reveals potential sources of bistability across the perceptual hierarchy

Perceptual bistability--the spontaneous fluctuation of perception between two interpretations of a stimulus--occurs when observing a large variety of ambiguous stimulus configurations. This phenomenon has the potential to serve as a tool for, among other things, understanding how function varies across individuals due to the large individual differences that manifest during perceptual bistability. Yet it remains difficult to interpret the functional processes at work, without knowing where bistability arises during perception. In this study we explore the hypothesis that bistability originates from multiple sources distributed across the perceptual hierarchy. We develop a hierarchical model of auditory processing comprised of three distinct levels: a Peripheral, tonotopic analysis, a Central analysis computing features found more centrally in the auditory system, and an Object analysis, where sounds are segmented into different streams. We model bistable perception within this system by injecting adaptation, inhibition and noise into one or all of the three levels of the hierarchy. We evaluate a large ensemble of variations of this hierarchical model, where each model has a different configuration of adaptation, inhibition and noise. This approach avoids the assumption that a single configuration must be invoked to explain the data. Each model is evaluated based on its ability to replicate two hallmarks of bistability during auditory streaming: the selectivity of bistability to specific stimulus configurations, and the characteristic log-normal pattern of perceptual switches. Consistent with a distributed origin, a broad range of model parameters across this hierarchy lead to a plausible form of perceptual bistability. The ensemble also appears to predict that greater individual variation in adaptation and inhibition occurs in later stages of perceptual processing.\n\nAuthor summaryOur ability to experience the everyday world through our senses requires that we resolve numerous ambiguities present in the physical evidence available. This is accomplished, in part, through a series of hierarchical computations, in which stimulus interpretations grow increasingly abstract. Our ability to resolve ambiguity does not always succeed, such as during optical illusions. In this study, we examine a form of perceptual ambiguity called bistability--cases in which a single individuals perception spontaneously switches back and forth between two interpretations of a single stimulus. A challenge in understanding bistability is that we dont know where along the perceptual hierarchy it is generated. Here we test the idea that there are multiple origins by building a simulation of the auditory system. Consistent with a multi-source account of bistability, this simulation accurately predicts perception of a simple auditory stimulus when bistability originates from a number of different sources within the model. The data also indicate that individual differences during ambiguous perception may primarily originate from higher levels of the perceptual hierarchy. This result provides a clue for future work aiming to determine how auditory function differs across individual brains.

animal behavior and cognition↗

bioRxiv2019

Adult-born neurons inhibit developmentally-born neurons in the dentate gyrus

During hippocampal-dependent memory formation, sensory signals from the neocortex converge in the dentate gyrus. It is generally believed that the dentate gyrus decorrelates inputs in order to minimize interference between codes for similar experiences, often referred to as pattern separation. Emerging evidence from mouse models suggests that adult-born neurons exert an inhibitory influence on the dentate gyrus, which may be important for maintaining the sparse code that is needed to form precise memories. However, since the dentate gyrus is composed of a heterogeneous population of cells that are born throughout life, it is unclear if newborn neurons inhibit all cells equally. We therefore investigated whether adult neurogenesis in rats modulates activity in dentate gyrus neurons that are born at the peak of early postnatal development. Adult neurogenesis was increased by subjecting rats to an alternating running and memantine treatment schedule, and it was decreased with a transgenic GFAP-TK rat model. Activity was measured by quantifying experience-induced Fos expression in BrdU+ cells. Consistent with an inhibitory role, enhancing neurogenesis blocked experience-dependent Fos expression in developmentally-born neurons and also in the broader granule cell population. In contrast, blocking neurogenesis did not significantly impact activity patterns. These results confirm previous work in mice and identify the developmentally-born population of neurons as a major target of neurogenesis-mediated inhibition. Treatments that target neurogenesis may therefore benefit disorders that are characterized by excitation-inhibition imbalance in the hippocampus, such as age-related memory impairments, fear and anxiety, and epilepsy.

neuroscience↗

bioRxiv2018

Hippocampal neurogenesis promotes preference for future rewards

Adult hippocampal neurogenesis is implicated in a number of disorders where reward processes are disrupted but whether new neurons regulate specific reward behaviors remains unknown. We find that blocking neurogenesis in rats reduces activation of the ventral dentate gyrus and causes a profound aversion for delayed rewards. Delay-based decision-making restructured dendrites and spines in adult-born neurons, consistent with activity-dependent neuronal recruitment. These findings identify a novel role for neurogenesis in decisions about future rewards, which is compromised in disorders where short-sighted gains are preferred at the expense of long-term health.

neuroscience↗

bioRxiv2018

Differential effects of extended exercise and memantine treatment on adult neurogenesis in male and female rats

The creation of new neurons in adulthood has potential for treating a number of disorders that are characterized by neurodegeneration or impaired plasticity. Animal models of reduced neurogenesis, and studies of the volume and structural integrity of the hippocampus in humans, suggest a possible therapeutic role for adult neurogenesis in age-related cognitive decline, depression, and schizophrenia. Research over the past 20 years has identified a number of approaches for enhancing adult neurogenesis, such as exercise, NMDA receptor antagonists, antidepressant drugs and environmental enrichment. However, despite the chronic nature of many disorders that impact the human hippocampus, most animal studies have only examined the efficacy of neurogenic treatments over relatively short timescales ([~]1 month or less). Additionally, investigations into the regulation of neurogenesis typically include only 1 sex, even though many disorders that affect the hippocampus differentially impact males and females. Here, we therefore tested whether two known pro-neurogenic treatments, running and the NMDA receptor antagonist, memantine, could lead to long-term increases in neurogenesis in male and female rats. We found that continuous access to a running wheel (cRUN) initially increased neurogenesis in both sexes, but effects were minimal after 1 month (both sexes) and completely absent after 5 months (males). Similarly, a single injection of memantine (sMEM) only transiently increased adult neurogenesis in both males and females. To determine whether extended increases in neurogenesis were possible with 2 months of RUN and MEM treatments, we subjected rats to interval running (iRUN), weekly memantine injections (mMEM), or combined treatments (iRUN-mMEM, mMEM-iRUN). We found that 2 months of iRUN increased DCX+ cell density in females but iRUN-mMEM treatment increased DCX+ cell density in males. However, analyses with thymidine analogs revealed that neurogenesis was minimally increased during the initial phases of the 2 month treatments. Collectively, our findings identify sex differences in the efficacy of neurogenic manipulations, which may be relevant for designing plasticity-promoting treatments that target the hippocampus.

neuroscience↗

bioRxiv2018

Intact memory for local and distal cues in male and female rats that lack adult neurogenesis

The dentate gyrus is essential for remembering the fine details of experiences that comprise episodic memory. Dentate gyrus granule cells receive highly-processed sensory information and are hypothesized to perform a pattern separation function, whereby similar sensory inputs are transformed into orthogonal neural representations. Behaviorally, this is believed to enable distinct memory for highly interfering stimuli. Since the dentate gyrus is comprised of a large number of adult-born neurons, which have unique synaptic wiring and neurophysiological firing patterns, it has been proposed that neurogenesis may contribute to this process in unique ways. Some behavioral evidence exists to support this role, whereby neurogenesis-deficient rodents are impaired at discriminating the fine visuospatial details of experiences. However, the extent to which newborn neurons contribute to dentate gyrus-dependent learning tasks is unclear. Furthermore, since most studies of dentate gyrus function are conducted in male rats, little is known about how females perform in similar situations, and whether there might be sex differences in the function of adult neurogenesis. To address these issues, we examined spatial discrimination memory in transgenic male and female rats that lacked adult neurogenesis. The first task probed memory for the position of local objects in an open field, assessed by behavioral responses to novel object locations. The second task examined memory for distal environmental cues. All rats were able to successfully discriminate local and distal cue changes. Males and females also performed comparably, although females displayed higher levels of rearing and locomotion. Collectively, our results indicate that rats are capable of learning about local and distal cues in the absence of adult neurogenesis.

neuroscience↗

bioRxiv2017

Running Promotes Spatial Bias Independently Of Adult Neurogenesis

Different memory systems offer distinct advantages to navigational behavior. The hippocampus forms complex associations between environmental stimuli, enabling flexible navigation through space. In contrast, the dorsal striatum associates discrete cues and favorable behavioral responses, enabling habit-like, automated navigation. While these two systems often complement one another, there are instances where striatal-dependent responses (e.g. approach a cue) conflict with hippocampal representations of spatial goals. In conflict situations, preference for spatial vs. response strategies varies across individuals and depends on previous experience, plasticity and the integrity of these two memory systems. Here, we investigated the role of adult hippocampal neurogenesis and exercise on mouse search strategies in a water maze task that can be solved with either a hippocampal-dependent place strategy or a striatal-dependent cue-response strategy. We predicted that inhibiting adult neurogenesis would impair hippocampal function and shift behavior towards striatal-dependent cue responses. However, blocking neurogenesis in a transgenic nestin-TK mouse did not affect strategy choice. We then investigated whether a pro-neurogenic stimulus, running, would bias mice towards hippocampal-dependent spatial strategies. While running indeed promoted spatial strategies, it did so even when neurogenesis was inhibited in nestin-TK mice. These findings indicate that exercise-induced increases in neurogenesis are not always required for enhanced cognitive function. Furthermore, our data identify exercise as a potentially useful strategy for promoting flexible, cognitive forms of memory in habit-related disorders that are characterized by excessive responding to discrete cues.

neuroscience↗