Biology subjects

Reynolds, J. H.

Publications and source records attributed to Reynolds, J. H..

5 recordsLinked to original sources

bioRxiv2022

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

Working memory relies critically on the dorsolateral prefrontal cortex (dlPFC). Morphology and function of the dlPFC, and corresponding working memory performance, are affected early in the aging process. However, these effects are heterogeneous, with nearly half of aged individuals spared of working memory deficits. Translationally relevant model systems are critical for investigating the neurobiological drivers of this variability and identifying why some people experience age-related working memory impairment while others do not. The common marmoset (Callithrix jacchus) is advantageous as a model in which to investigate the biological underpinnings of aging because, as a nonhuman primate, marmosets have a clearly defined dlPFC facilitating investigations of prefrontal-dependent cognitive functions, including working memory, and their short (~10 year) lifespan facilitates longitudinal studies of aging. Here, we conduct the first investigation of synaptic ultrastructure in the dlPFC of the marmoset and investigate whether there are changes to synaptic ultrastructure that are unique to aging with and without working memory impairment. To do this, we characterized working memory capacity in a cohort of marmosets that collectively covered their short lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Utilizing three dimensional reconstruction from serial section electron microscopy, we visualized structural correlates of synaptic efficacy including boutons, mitochondria, and synapses in layer III of the dlPFC of three marmosets: one young adult (YA), one aged cognitively unimpaired (AU), and one aged cognitively impaired (AI). We find that aged marmosets have fewer synapses in dlPFC than young, and this is due to selective vulnerability of small synapses. Next, we tested the hypothesis that violation of the ultrastructural size principle underlies age-related working memory impairment. The ultrastructural size principle states that synaptic efficacy relies on coordinated scaling of synaptic components (e.g., synapses, mitochondria) with presynaptic boutons. While synapses and mitochondria scaled proportionally and were strongly correlated with presynaptic boutons in the YA and AU marmosets, the ultrastructural characteristics of the AI marmoset were alarmingly different. We found that age-related working memory impairment was associated with disproportionately large synapses compared to presynaptic boutons, specifically in those with mitochondria. Remarkably, presynaptic mitochondria and these boutons were completely decorrelated. We posit that this decorrelation results in mismatched energy supply and demand, leading to impaired synaptic transmission. This is the first report of age-related synapse loss in the marmoset, and the first demonstration that violation of the ultrastructural size principle underlies age-related working memory impairment.

neuroscience↗

bioRxiv2022

Mechanisms underlying reshuffling of visual responses by optogenetic stimulation in mice and monkeys

The ability to optogenetically perturb neural circuits opens an unprecedented window into mechanisms governing circuit function. We analyzed and theoretically modeled neuronal responses to visual and optogenetic inputs in mouse and monkey V1. In both species, optogenetic stimulation of excitatory neurons strongly modulated the activity of single neurons, yet had weak or no effects on the distribution of firing rates across the population. Thus, the optogenetic inputs reshuffled firing rates across the network. Key statistics of mouse and monkey responses lay on a continuum, with mice/monkeys occupying the low/high rate regions, respectively. We show that neuronal reshuffling emerges generically in randomly connected excitatory/inhibitory networks, provided the coupling strength (combination of recurrent coupling and external input) is sufficient that powerful inhibitory feedback cancels the mean optogenetic input. A more realistic model, distinguishing tuned visual vs. untuned optogenetic input in a structured network, reduces the coupling strength needed to explain reshuffling.

neuroscience↗

bioRxiv2022

Age-related learning and working memory impairment in the common marmoset

Aging is the greatest risk factor for the development of neurodegenerative diseases, yet we still do not understand how the aging process leads to pathological vulnerability. The research community has relied heavily on mouse models, but the considerable anatomical, physiological, and cognitive differences between mice and humans limit their translational relevance. Ultimately, these barriers necessitate the development of novel aging models. As a non-human primate, the common marmoset (Callithrix jacchus) shares many features in common with humans and yet has a significantly shorter lifespan (10 years) than other primates, making it ideally suited to longitudinal studies of aging. Our objective was to evaluate the marmoset as a model of age-related cognitive impairment. To do this, we utilized the Delayed Recognition Span Task (DRST) to characterize age-related changes in working memory capacity in a cohort of sixteen marmosets varying in age from young adult to geriatric. These monkeys performed thousands of trials over periods of time ranging up to 50 percent of their adult lifespan. To our knowledge, this represents the most thorough cognitive profiling of any marmoset aging study conducted to-date. By analyzing individual learning curves, we found that aged animals exhibited delayed onset of learning, slowed learning rate after onset, and decreased asymptotic working memory performance. These findings are not accounted for by age-related impairments in motor speed and motivation. This work firmly establishes the marmoset as a model of age-related cognitive impairment. Significance StatementUnderstanding the normal aging process is fundamental to identifying therapeutics for neurodegenerative diseases for which aging is the biggest risk factor. Historically, the aging field has relied on animal models that differ markedly from humans, constraining translatability. Here, we firmly establish a short-lived non-human primate, the common marmoset, as a key model of age-related cognitive impairment. We demonstrate, through continuous testing over a substantial portion of the adult marmoset lifespan, that aging is associated with both impaired learning and working memory capacity, unaccounted for by age-related changes in motor speed and motivation. Characterizing individual cognitive aging trajectories reveals inherent heterogeneity, which could lead to earlier identification of the onset of impairment, and extended timelines during which therapeutics are effective.

neuroscience↗

bioRxiv2021

Brain state and cortical layer-specific mechanisms underlying perception at threshold

Identical stimuli can be perceived or go unnoticed across successive presentations, producing divergent behavioral outcomes despite similarities in sensory input. We sought to understand how fluctuations in behavioral state and cortical layer and cell-class specific neural activity underlie this perceptual variability. We analyzed physiological measurements of state and laminar electrophysiological activity in visual area V4 while monkeys were rewarded for correctly reporting a stimulus change at perceptual threshold. Hit trials were characterized by a behavioral state with heightened arousal, greater eye position stability, and enhanced decoding performance of stimulus identity from neural activity. Target stimuli evoked stronger responses in V4 in hit trials, and excitatory neurons in the superficial layers, the primary feed-forward output of the cortical column, exhibited lower variability. Feed-forward interlaminar population correlations were stronger in hits. Hit trials were further characterized by greater synchrony between the output layers of the cortex during spontaneous activity, while the stimulus-evoked period showed elevated synchrony in the feed-forward pathway. Taken together, these results suggest that a state of elevated arousal and stable retinal images allow enhanced processing of sensory stimuli, which contributes to hits at perceptual threshold.

neuroscience↗

bioRxiv2021

Columnar processing of border ownership in primate visual cortex

To understand a visual scene, the brain segregates figures from background by assigning borders to foreground objects. Neurons in primate visual cortex encode which object owns a border (border ownership), but the underlying circuitry is not understood. Here we used multielectrode probes to record from border ownership selective units in different layers in macaque visual area V4 to study the laminar organization and timing of border ownership selectivity. We find that border ownership selectivity occurs first in deep layer units, in contrast to spike latency for small stimuli in the classical receptive field. Units on the same penetration typically share the preferred side of border ownership, also across layers, similar to orientation preference. Units are often border ownership selective for a range of border orientations, where the preferred sides of border ownership are systematically organized in visual space. Together our data reveal a columnar organization of border ownership in V4 where the earliest border ownership signals are not simply inherited from upstream areas, but computed by neurons in deep layers, and may thus be part of signals fed back to upstream cortical areas or the oculomotor system early after stimulus onset. The finding that preferred border ownership is clustered and can cover a wide range of spatially contiguous locations, suggests that the asymmetric context integrated by these neurons is provided in a systematically clustered manner, possibly through corticocortical feedback and horizontal connections.

neuroscience↗