Understanding the causal relationship between neural activity and behavior requires the ability to perform rapid and targeted interventions in ongoing activity. Here we describe a closed-loop ...all-optical strategy for dynamically controlling neuronal activity patterns in awake mice. We rapidly tailored and delivered two-photon optogenetic stimulation based on online readout of activity using simultaneous two-photon imaging, thus enabling the manipulation of neural circuit activity 'on the fly' during behavior.
Solid organ transplant recipients may be at a high risk for SARS‐CoV‐2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with ...SARS‐CoV‐2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty‐six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual‐organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty‐two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non‐rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID‐19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID‐19 has the potential to severely impact solid organ transplant recipients.
In this multicenter study of 90 solid organ transplant recipients diagnosed with COVID‐19 during the first three weeks of the outbreak in New York City, the authors report on the clinical presentation, laboratory abnormalities, risk factors, disease severity, and outcomes.
The hippocampus is crucial for spatial navigation and episodic memory formation. Hippocampal place cells exhibit spatially selective activity within an environment and have been proposed to form the ...neural basis of a cognitive map of space that supports these mnemonic functions. However, the direct influence of place cell activity on spatial navigation behavior has not yet been demonstrated. Using an ‘all-optical’ combination of simultaneous two-photon calcium imaging and two-photon optogenetics, we identified and selectively activated place cells that encoded behaviorally relevant locations in a virtual reality environment. Targeted stimulation of a small number of place cells was sufficient to bias the behavior of animals during a spatial memory task, providing causal evidence that hippocampal place cells actively support spatial navigation and memory.
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•Two-photon optogenetics in VR enables targeted manipulation of place cell ensembles•Activating specific place cell ensembles drives their spatially associated behavior•Place cell stimulation inhibits endogenous place code expression and triggers remapping•Direct evidence for a causal role of place cells in spatial navigation
Selective stimulation of a small number of hippocampal place cells in mice provides causal evidence that hippocampal place cells actively support spatial navigation and memory.
We describe an all-optical strategy for simultaneously manipulating and recording the activity of multiple neurons with cellular resolution in vivo. We performed simultaneous two-photon optogenetic ...activation and calcium imaging by coexpression of a red-shifted opsin and a genetically encoded calcium indicator. A spatial light modulator allows tens of user-selected neurons to be targeted for spatiotemporally precise concurrent optogenetic activation, while simultaneous fast calcium imaging provides high-resolution network-wide readout of the manipulation with negligible optical cross-talk. Proof-of-principle experiments in mouse barrel cortex demonstrate interrogation of the same neuronal population during different behavioral states and targeting of neuronal ensembles based on their functional signature. This approach extends the optogenetic toolkit beyond the specificity obtained with genetic or viral approaches, enabling high-throughput, flexible and long-term optical interrogation of functionally defined neural circuits with single-cell and single-spike resolution in the mouse brain in vivo.
Most population-based estimates of incident hospitalized heart failure (HF) have not differentiated acute decompensated heart failure (ADHF) from chronic stable HF nor included racially diverse ...populations. The Atherosclerosis Risk in Communities Study conducted surveillance of hospitalized HF events (age ≥55 years) in 4 US communities. We estimated hospitalized ADHF incidence and survival by race and gender. Potential 2005 to 2009 HF hospitalizations were identified by International Classification of Diseases, Ninth Revision, Clinical Modification , codes; 6,168 records were reviewed to validate ADHF cases. Population estimates were derived from US Census data; 50% of eligible hospitalizations were classified as ADHF, of which 63.6% were incident ADHF and 36.4% were recurrent ADHF. The average incidence of hospitalized ADHF was 11.6 per 1,000 persons, aged ≥55 years, per year, and recurrent hospitalized ADHF was 6.6 per 1,000 persons/yr. Age-adjusted annual ADHF incidence was highest for black men (15.7 per 1,000), followed by black women (13.3 per 1,000), white men (12.3 per 1,000), and white women (9.9 per 1,000). Of incident ADHF events with heart function assessment (89%), 53% had reduced the ejection fraction (heart failure with reduced ejection fraction HFrEF) and 47% had preserved ejection fraction (heart failure with preserved ejection fraction HFpEF). Black men had the highest proportion of acute HFrEF events (70%); white women had the highest proportion of acute HFpEF (59%). Age-adjusted 28-day and 1-year case fatality after an incident ADHF was 10.4% and 29.5%, respectively. Survival did not differ by race or gender. In conclusion, ADHF hospitalization and HF type varied by both race and gender, but case fatality rates did not. Further studies are needed to explain why black men are at higher risk of hospitalized ADHF and HFrEF.
Many theories of brain function propose that activity in sparse subsets of neurons underlies perception and action. To place a lower bound on the amount of neural activity that can be perceived, we ...used an all-optical approach to drive behaviour with targeted two-photon optogenetic activation of small ensembles of L2/3 pyramidal neurons in mouse barrel cortex while simultaneously recording local network activity with two-photon calcium imaging. By precisely titrating the number of neurons stimulated, we demonstrate that the lower bound for perception of cortical activity is ~14 pyramidal neurons. We find a steep sigmoidal relationship between the number of activated neurons and behaviour, saturating at only ~37 neurons, and show this relationship can shift with learning. Furthermore, activation of ensembles is balanced by inhibition of neighbouring neurons. This surprising perceptual sensitivity in the face of potent network suppression supports the sparse coding hypothesis, and suggests that cortical perception balances a trade-off between minimizing the impact of noise while efficiently detecting relevant signals.
The mechanistic link between neural circuit activity and behavior remains unclear. While manipulating cortical activity can bias certain behaviors and elicit artificial percepts, some tasks can still ...be solved when cortex is silenced or removed. Here, mice were trained to perform a visual detection task during which we selectively targeted groups of visually responsive and co-tuned neurons in L2/3 of primary visual cortex (V1) for two-photon photostimulation. The influence of photostimulation was conditional on two key factors: the behavioral state of the animal and the contrast of the visual stimulus. The detection of low-contrast stimuli was enhanced by photostimulation, while the detection of high-contrast stimuli was suppressed, but crucially, only when mice were highly engaged in the task. When mice were less engaged, our manipulations of cortical activity had no effect on behavior. The behavioral changes were linked to specific changes in neuronal activity. The responses of non-photostimulated neurons in the local network were also conditional on two factors: their functional similarity to the photostimulated neurons and the contrast of the visual stimulus. Functionally similar neurons were increasingly suppressed by photostimulation with increasing visual stimulus contrast, correlating with the change in behavior. Our results show that the influence of cortical activity on perception is not fixed, but dynamically and contextually modulated by behavioral state, ongoing activity and the routing of information through specific circuits.
Sensory processing in the neocortex requires both feedforward and feedback information flow between cortical areas
. In feedback processing, higher-level representations provide contextual ...information to lower levels, and facilitate perceptual functions such as contour integration and figure-ground segmentation
. However, we have limited understanding of the circuit and cellular mechanisms that mediate feedback influence. Here we use long-range all-optical connectivity mapping in mice to show that feedback influence from the lateromedial higher visual area (LM) to the primary visual cortex (V1) is spatially organized. When the source and target of feedback represent the same area of visual space, feedback is relatively suppressive. By contrast, when the source is offset from the target in visual space, feedback is relatively facilitating. Two-photon calcium imaging data show that this facilitating feedback is nonlinearly integrated in the apical tuft dendrites of V1 pyramidal neurons: retinotopically offset (surround) visual stimuli drive local dendritic calcium signals indicative of regenerative events, and two-photon optogenetic activation of LM neurons projecting to identified feedback-recipient spines in V1 can drive similar branch-specific local calcium signals. Our results show how neocortical feedback connectivity and nonlinear dendritic integration can together form a substrate to support both predictive and cooperative contextual interactions.
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