Journal of Neuroscience最新文献

Given the prevalence of alcohol use and stress during pregnancy, we examined the effects in offspring of prenatal alcohol and stress on the dopamine system and drinking behavior in a primate model. In a 20-year prospective longitudinal experiment, we studied alcohol-naive adult rhesus monkeys of both sexes bred from mothers randomly assigned during pregnancy to consume moderate alcohol, be exposed to mild stress, both, or neither. Positron emission tomography (PET) was used to measure dopamine D₂-type receptor (D2) and transporter (DAT) availability in substantia nigra/ventral tegmental area (SN/VTA), striatum, and prefrontal cortex (PFC), at baseline and after chronic fixed-dose drinking in offspring. After the follow-up PET scans, monkeys were given ad libitum access to alcohol. Findings were: (1) prenatal stress increased DAT in SN/VTA and striatum, while an interaction of prenatal stress and alcohol altered D2 in PFC; (2) prenatal alcohol alone increased the fixed-dose drinking rate; (3) in the three brain regions, low baseline D2 predicted faster fixed-dose drinking rate, and changes in DAT from baseline to follow-up predicted consumption in subsequent ad libitum drinking; and (4) no significant alteration of D2 or DAT due to drinking was observed. This experiment highlights the sensitivity of the primate dopamine system to prenatal perturbations, dopamine's role in drinking, and an individual neuroadaptive response to chronic alcohol consumption. The results suggest that alcohol abuse may originate, in part, from prenatal alcohol exposure. Moreover, reports in AUD of lower D2 might reflect preexisting dopamine receptor status rather than resulting entirely from alcohol consumption.

The photothrombotic stroke model is gaining popularity due to its relative simplicity, minimal invasiveness, and clinical relevance. Photothrombosis involves the delivery of an intravascular photosensitizer (Rose Bengal) followed by its photoactivation, resulting in vessel occlusion and ischemia. Using a combination of complementary optical and non-optical techniques, we characterized the physiological changes in mice undergoing photothrombosis. We report that Rose Bengal has vasoconstrictive properties, inducing hypoemia both in the brain and periphery even in the absence of its photoactivation. Conversely, we find that light, when used at photothrombosis-appropriate intensities and durations, induces large amounts of tissue heating and hyperemia even in the distal non-illuminated hemisphere. Furthermore, we show that use of the optimal photothrombotic wavelength based on the Rose Bengal absorption spectrum (yellow-561nm) produces a more consistent and pronounced drop in blood flow, and a shorter latency to the initial spreading depolarization (SD), ultimately resulting in a larger stroke. Similarly, when yellow light is used to induce a stroke in ChR2-expressing mice, the electrophysiological and hemodynamic confounds from green light cross activation of ChR2 are eliminated. Finally, we observe across cohorts that male mice have larger strokes than females. Altogether, we extensively describe important caveats and confounds concerning photothrombosis and provide a detailed characterization of its early ischemic events.Significance statement Photothrombosis is a powerful model of ischemic stroke which uses light to photoactivate an intravascular dye (Rose Bengal). However, little is known about the independent effects of both the Rose Bengal and the light used to activate it. We show that both manipulations introduce separate confounds relevant to stroke outcomes, something which should be considered and accounted for when using this technique. In addition, we demonstrate that by using the optimal Rose Bengal excitation wavelength, the blood flow drop is more pronounced and consistent, resulting in larger strokes. Furthermore, we show that precautions can be taken to avoid spectral overlap when integrating photothrombosis in optogenetic experiments. Finally, we explore sex differences in lesion volume.

Visual attention is shaped by statistical regularities in the environment, with spatially predictable distractors being proactively suppressed. The neural mechanisms underpinning this suppression remain poorly understood. In this study, we employed magnetoencephalography and multivariate classification analysis to investigate how predicted distractor locations are proactively processed in the human brain. Male and female human participants engaged in a statistical learning visual search task that required them to identify a target stimulus while ignoring a color-singleton distractor. Critically, the distractor appeared more frequently on one side of the visual field, creating an implicit spatial prediction. Our results revealed that distractor locations were encoded in temporo-occipital brain regions prior to the presentation of the search array, supporting the hypothesis that proactive suppression guides visual attention away from predictable distractors. The neural activity patterns corresponding to this presearch distractor processing extended to postsearch activity during late attentional stages (∼200 ms), suggesting an integrated suppressive mechanism. Notably, this generalization from pre- to postsearch phases was absent in the early sensory processing stages (∼100 ms), suggesting that postsearch distractor processing is not merely a continuation of sustained proactive processing but involves re-engagement of the same mechanism at distinct stages. These findings establish a mechanistic link between proactive and reactive processing of predictable distractors, demonstrating both shared and unique contributions to attentional selection.

Executive dysfunction can precede the accumulation of canonical neuropathological markers and severe dementia in Alzheimer's disease (AD) patients often characterized by memory changes. Deficits in executive function including flexible behavior, i.e., the ability to shift behavior following negative consequences, are often mediated by the prefrontal cortex. However, it is unknown how medial prefrontal cortex activity is altered in behaving Tg-F344-AD rats, which exhibit age-dependent AD pathology and memory deficits. We tested the ability of in 6-7-month-old TgF344-AD rats to learn reward predictive cues and to shift behavior away from cues following outcome devaluation while recording mPFC neurons (wild-type, 10 males and 7 females; TgF344-AD, 8 males and 9 females). Rats were presented with two distinct cues as conditioned stimuli (CS+) predicting two distinct outcomes over learning. Then, a conditioned taste aversion to one outcome was induced, and rats were evaluated for their ability to avoid the CS+ associated with the devalued outcome. We found a loss of motivated behavior during learning and impaired flexible behavior in 6-7-month-old AD rats relative to controls. In addition, there was differential aberrant mPFC encoding of cue-outcome associations in AD rats during conditioning and following devaluation. AD rats showed fewer neurons during conditioning that encode both the cue and the outcome. Also, AD rats showed a greater proportion of neurons that exhibited an excited response to reward predictive cues following devaluation. Together, these data contribute to our understanding of alterations in mPFC that may underlie prodromal AD behavioral deficits to inform future treatments.

In visually complex and dynamically changing environments, humans must often filter out salient but task-irrelevant stimuli. Prior work shows that with repeated exposure to color singleton distractors, individuals can learn to divert attention away from these salient items. However, the neural mechanisms supporting such attentional suppression remain unclear. The present study examined the temporal trajectories of singleton distractor representations during visual search to address this gap. Using multivariate pattern analyses of EEG data in human subjects (N = 40, 30 females, 10 males), we identified two clusters of decodable singleton distractor representations: an early cluster from 100-200 ms and a later cluster from 200-400 ms. Temporal generalization analyses showed that the later representations were inverted versions of the early ones. Importantly, stronger late, but not early representations, predicted faster search responses, suggesting that the later signals support distractor suppression. This representational inversion facilitates suppressing singleton distractors in the spatial priority map. Comparing decoding evidence across locations revealed that singleton distractor locations were suppressed relative to non-singleton distractors. Moreover, comparing the neural coding of locations revealed that the spatial organization in the singleton distractor neural space was inverted relative to that in the target neural space. Together, these findings reveal a rapid representational inversion underlying salient distractor suppression at the onset of visual search. This inversion of singleton distractor signals was likely driven by top-down control mechanisms that transform bottom-up saliency signals, producing an inverted arrangement of target and distractor information within a shared neural space.Significance Statement A primary goal of attention is to select relevant information while ignoring irrelevant input from the external environment. Although the mechanisms of attentional enhancement have been extensively studied, the mechanisms underlying attentional suppression remain less well understood. While prior work has made important progress in identifying when attentional suppression is engaged, the neural mechanisms that implement suppression are still unclear. Here, we show that neural representations of salient singleton distractors undergo a rapid inversion approximately 200 ms after search onset. These inverted representations can subsequently be read out as suppression signals during the computation of spatial priorities. Together, our findings suggest that transforming initial pop-out distractor signals into an inverted representational format might drive rapid attentional suppression and support goal-directed visual search.

Neurons in the lateral hypothalamic area (LHA) are critical drivers of behavioral and physiological responses to acute and chronic stress. However, the roles of the specific presynaptic inputs to the LHA in driving stress and resultant physiological effects are yet to be fully understood. Here, leveraging intersectional viral genetics, optogenetics, chemogenetics, and fiber photometry, we show that the excitatory projections from the rostral ventromedial medulla (RVM) to LHA drive anxiety-like behaviors in male and female mice. This is a surprising finding since, traditionally, RVM has been studied in the context of opioidergic pain modulation through its inhibitory projections to the spinal cord. We find that the LHA neurons receiving inputs from the RVM, when activated, do not alter the nociceptive thresholds yet are sufficient to drive anxiety-like behaviors. These LHA neurons are recruited by acute restraint, which is known to cause stress and anxiety. On the other hand, the LHA-projecting RVM neurons are responsive to both noxious thermal stimuli and acute restraint, promoting anxiety, yet with no effect on pain thresholds. Our findings provide evidence that a distinct ascending circuitry, from RVM to LHA, is instrumental in driving aversion and anxiety-like behaviors in mice without affecting nociceptive thresholds.

How aging affects brain-body connections can be investigated through changes in the coupling between functional magnetic resonance imaging (fMRI) signals and bodily autonomic processes across the adult lifespan. Recent studies using univariate approaches have identified age-related changes in the association between fMRI signals from multiple individual brain regions and low-frequency respiratory and cardiac activity. Here, we investigate if whole-brain spatial fMRI patterns associated with low-frequency physiological processes (heart rate and respiratory volume fluctuations) present generalizable changes with age. Data from human participants of both sexes are included in the analysis. We find that chronological age can be predicted statistically beyond chance from patterns of low-frequency fMRI-physiological coupling, even after accounting for individual differences in physiological signal characteristics and brain anatomy. Notably, brain areas implicated in central autonomic regulation, including nodes within salience and ventral attention networks (e.g., insula and middle cingulate cortex), are among the strongest contributors to age prediction. Furthermore, we observe that after removing physiological effects from fMRI data, the residual blood oxygen level-dependent signal variability is still a reliable indicator of age. Together, these findings underscore the close integration between brain and body physiology and highlight this interaction as a potential biomarker of the aging process.

Establishing learned associations between rewarding stimuli and the context under which those rewards are encountered is critical for survival. Hippocampal input to the nucleus accumbens (NAc) provides important environmental context to reward processing to support goal-directed behaviors. This connection consists of two independent pathways originating from the dorsal (dHipp) or ventral (vHipp) hippocampus, which have previously been considered functionally and anatomically distinct. Here, we show overlap in dHipp and vHipp terminal fields in the NAc, leading us to reconsider this view and raise new questions regarding the potential interactions between dHipp and vHipp pathways in the NAc. Using optogenetics, electrophysiology, and transsynaptic labeling in male and female mice, we investigated anatomical and functional convergence of dHipp and vHipp inputs in the NAc. Transsynaptic labeling revealed a subpopulation of dually innervated cells in the NAc medial shell, confirmed by independent optogenetic manipulation of dHipp and vHipp inputs during whole-cell electrophysiological recordings. Further analysis revealed closely apposed dHipp and vHipp inputs along dendritic branches, and simultaneous stimulation of both inputs elicited heterosynaptic potentiation. Comparison of observed and theoretical success rates suggests heterosynaptic interactions may occur presynaptically. Altogether, these results demonstrate that inputs originating from dHipp and vHipp converge onto a subset of NAc neurons with synapses positioned to enable rapid heterosynaptic interactions, indicating integration of these inputs at the single-neuron level. Exploring the physiological and behavioral implications of this convergence will offer new insights into how individual neurons incorporate information from distinct inputs and how this integration may shape learning.Significance statement Linking rewards to the contexts in which they are experienced is vital for survival. Hippocampal (Hipp) input to the nucleus accumbens (NAc) is essential for associating rewards with their environmental context to effectively guide motivated behaviors. This connection consists of two separate pathways originating from dorsal and ventral Hipp that have long been considered distinct. Here, we reveal a subpopulation of neurons in the NAc shell innervated by both Hipp subregions and heterosynaptic interactions that occur between dorsal and ventral Hipp-NAc synapses. These findings suggest that integration of distinct hippocampal information occurs at the single-neuron level, providing a critical mechanism underlying learning and motivated behavior while also opening new avenues for understanding how diverse contextual and reward signals shape decision-making.

Processing ordinality, i.e., the rank of an item in a series such as 1^st, 2^nd, 3^rd, etc., is a fundamental skill shared by humans and animals. While humans often use symbolic sequences like numbers or letters, ordinality does not depend on language or symbols. Across species, ordinality plays a critical role in behaviors such as decision-making, foraging, and social organization. We hypothesize that ordinality perception is supported by neuronal tuning, i.e., neurons selectively responsive to specific ranks. Using ultra-high field 7T fMRI and population receptive field (pRF) modeling in human participants (both female and male), we identified neural populations in parietal and premotor cortices that are tuned to non-symbolic ordinal positions. Comparable to other sensory domains, tuning width increased with preferred ordinal rank, suggesting reduced precision and potentially lower perceptual accuracy for higher ranks. Additionally, pRF measurements revealed that cortical territory devoted to higher ordinalities decreased with rank, reinforcing that neural precision is greatest for early positions (e.g., 1st and 2nd) and declines with rank. These responses did not generalize to symbolic ordinality. Similar tuning to non-symbolic ordinality emerged spontaneously in hierarchical convolutional neural networks trained on visual tasks. Together, these results suggest that the tuning properties of these neuronal populations support non-symbolic ordinality perception, and may reflect an inherent feature of neural processing.Significance Statement Processing ordinality, the rank of items in sequences, is a fundamental skill shared across humans and animals that plays a role in decision-making, foraging, and social organization. We hypothesized that ordinality processing relies on neuronal tuning where neurons selectively respond to particular ranks. Using ultra-high field 7T fMRI and population receptive field modeling, we identified neural populations in parietal and premotor cortices tuned to non-symbolic ordinal positions. Additionally, similar tuning responses were found to spontaneously emerge in hierarchical convolutional neural networks trained on a visual task. Our findings demonstrate that akin to other forms of quantity representation, neuronal tuning underlies non-symbolic ordinality perception. These results shed light on the neuronal processing of ordinality in the human brain.

The small and tortuous volume of synaptic clefts limits the diffusion of Ca²⁺ ions during high frequency spiking. Extracellular Ca²⁺ levels ([Ca²⁺]_o) of 0.8 mM or lower have been measured or calculated for different synapses. Here, we recorded evoked postsynaptic potentials (EPSP) and action potentials (AP) from young adult male and female mouse auditory brainstem principal neurons to investigate the relationship between neurotransmission reliability, stimulation frequency and [Ca²⁺]_o In 0.8 mM [Ca²⁺]_o, we observed AP failures during stimulation at 100 Hz. Surprisingly, AP failures, EPSP-AP latency and jitter were all reduced when stimulation frequency was increased to 500 Hz. Analysis of the EPSP revealed marked facilitation at 500 Hz that was not present at 100 Hz. Raising [Ca²⁺]_o to 1.2 mM or 2.0 mM reduced or eliminated facilitation and, in these conditions that promote EPSP short-term depression, stimulation at 500 Hz increased the number of AP failures. In 0.8 mM Ca²⁺, stimulation over a range of frequencies from 10-1000 Hz produced heterogenous frequency responses. Some principal neurons were unable to evoke fail-safe AP firing during low frequency stimulation (10-100 Hz), but exhibited reliable firing at 300-500 Hz, which was rapid enough to activate EPSP facilitation. At frequencies above 600 Hz, all synapses began to express intermittent transmission failures. We conclude that synaptic facilitation can produce bandpass filtering in firing probability and contribute positively to the maintenance of reliable and precise high frequency neurotransmission in calyx of Held synapses.Significance Statement Facilitation of evoked postsynaptic currents is a common feature of synapses. The strength of facilitation and its role in reaching spike threshold depends on intrinsic properties of the synapse, stimulation frequency, and extracellular Ca²⁺ concentration ([Ca²⁺]_o). Physiological levels of [Ca²⁺]_o can vary from 0.8 to 1.2 mM depending on synaptic activity. In auditory calyx-type synapses, synaptic facilitation is readily observable in brainstem slices using relatively low (0.8 mM) [Ca²⁺]_o, but is partially or completely obscured by short-term synaptic depression when [Ca²⁺]_o is higher (1.2 or 2.0 mM). Here we show that short-term synaptic facilitation can rescue the reliability of high-frequency (500 Hz) action potential firing in low [Ca²⁺]_o.