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Neural circuits are made of a vast diversity of neuronal cell types. While immense progress has been made in classifying neurons based on morphological, molecular, and functional properties, understanding how this heterogeneity contributes to brain function during natural behavior has remained largely unresolved. In the present study, we combined the juxtacellular recording and labeling technique with optogenetics in freely moving mice. This allowed us to selectively target molecularly defined cell classes for in vivo single-cell recordings and morphological analysis. We validated this strategy in the CA1 region of the mouse hippocampus by restricting Channelrhodopsin expression to Calbindin-positive neurons. Directly versus indirectly light-activated neurons could be readily distinguished based on the latencies of light-evoked spikes, with juxtacellular labeling and post hoc histological analysis providing ‘ground-truth’ validation. Using these opto-juxtacellular procedures in freely moving mice, we found that Calbindin-positive CA1 pyramidal cells were weakly spatially modulated and conveyed less spatial information than Calbindin-negative neurons – pointing to pyramidal cell identity as a key determinant for neuronal recruitment into the hippocampal spatial map. Thus, our method complements current in vivo techniques by enabling optogenetic-assisted structure–function analysis of single neurons recorded during natural, unrestrained behavior.

The noradrenergic locus coeruleus (LC) is a controller of brain and behavioral states. Activating LC neurons en masse by electrical or optogenetic stimulation promotes a stereotypical “activated” cortical state of high-frequency oscillations. However, it has been recently reported that spontaneous activity of LC cell pairs has sparse yet structured time-averaged cross-correlations, which is unlike the highly synchronous neuronal activity evoked by stimulation. Therefore, LC population activity could consist of distinct multicell ensembles each with unique temporal evolution of activity. We used nonnegative matrix factorization (NMF) to analyze large populations of simultaneously recorded LC single units in the rat LC. NMF identified ensembles of spontaneously coactive LC neurons and their activation time courses. Since LC neurons selectively project to specific forebrain regions, we hypothesized that distinct ensembles activate during different cortical states. To test this hypothesis, we calculated band-limited power and spectrograms of local field potentials in cortical area 24a aligned to spontaneous activations of distinct LC ensembles. A diversity of state modulations occurred around activation of different LC ensembles, including a typical activated state with increased highfrequency power as well as other states including decreased high-frequency power. Thus—in contrast to the stereotypical activated brain state evoked by en masse LC stimulation—spontaneous activation of distinct LC ensembles is associated with a multitude of cortical states.

The brain’s ability to associate threats with external stimuli is vital to execute essential behaviours including avoidance. Disruption of this process contributes instead to the emergence of pathological traits which are common in addiction and depression. However, the mechanisms and neural dynamics at the single-cell resolution underlying the encoding of associative learning remain elusive. Here, employing a Pavlovian discrimination task in mice we investigate how neuronal populations in the lateral habenula (LHb), a subcortical nucleus whose excitation underlies negative affect, encode the association between conditioned stimuli and a punishment (unconditioned stimulus). Large population single-unit recordings in the LHb reveal both excitatory and inhibitory responses to aversive stimuli. Additionally, local optical inhibition prevents the formation of cue discrimination during associative learning, demonstrating a critical role of LHb activity in this process. Accordingly, longitudinal in vivo two-photon imaging tracking LHb calcium neuronal dynamics during conditioning reveals an upward or downward shift of individual neurons’ CS-evoked responses. While recordings in acute slices indicate strengthening of synaptic excitation after conditioning, support vector machine algorithms suggest that postsynaptic dynamics to punishment-predictive cues represent behavioral cue discrimination. To examine the presynaptic signaling in LHb participating in learning we monitored neurotransmitter dynamics with genetically-encoded indicators in behaving mice. While glutamate, GABA, and serotonin release in LHb remain stable across associative learning, we observe enhanced acetylcholine signaling developing throughout conditioning. In summary, converging presynaptic and postsynaptic mechanisms in the LHb underlie the transformation of neutral cues in valued signals supporting cue discrimination during learning.

The brainstem region, locus coeruleus (LC), has been remarkably conserved across vertebrates. Evolution has woven the LC into wide-ranging neural circuits that influence functions as broad as autonomic systems, the stress response, nociception, sleep, and high-level cognition among others. Given this conservation, there is a strong possibility that LC activity is inherently similar across species, and furthermore that age, sex, and brain state influence LC activity similarly across species. The degree to which LC activity is homogenous across these factors, however, has never been assessed due to the small sample size of individual studies. Here, we pool data from 20 laboratories (1,855 neurons) and show diversity across both intrinsic and extrinsic factors such as species, age, sex and brain state. We use a negative binomial regression model to compare activity from male monkeys, and rats and mice of both sexes that were recorded across brain states from brain slices or under different anesthetics or during wakefulness . LC activity differed due to complex interactions of species, sex, and brain state. The LC became more active during aging, independent of sex. Finally, in contrast to the foundational principle that all species express two distinct LC firing modes (\"tonic\" or \"phasic\"), we discovered great diversity within spontaneous LC firing patterns. Different factors were associated with higher incidence of some firing modes. We conclude that the activity of the evolutionarily-ancient LC is not conserved. Inherent differences due to age and species-sex-brain state interactions have implications for understanding the role of LC in species-specific naturalistic behavior, as well as in psychiatric disorders, cardiovascular disease, immunology, and metabolic disorders.

Contemporary neuroscience and psychiatry suggest that attention to decision outcomes guides rule learning by adjusting stimulus-outcome associations. Separately, sensory neurophysiology conceptualizes attention as a ‘filter’ that improves perception. Here, we show that the contemporary view is incomplete by demonstrating an unconventional and novel effect of perceptual attention on subsequent outcome-based rule learning. Moreover, we show for the first time in rodents that, like in primates, this attentional process involves tuning of modality specific cortico-cortical interactions. We designed a novel head-fixed rat-on-a-treadmill apparatus and used it to train rats to discriminate auditory-visual stimuli using one modality and then reduced stimulus discriminability in that modality. We observed perceptual learning suggesting engagement of perceptual attention. Moreover, engaging visual perceptual attention resulted in more saccades and increased frontal-visual cortex EEG Granger causality relative to engaging auditory perceptual attention. We then presented novel and easily discriminable stimuli in both modalities and measured outcome-driven learning in the other modality. Learning was slower after engaging perceptual attention. Our work suggests that a more complete description of learning requires integrating these previously siloed concepts of attention. Moreover, treating impaired set-shifting as a trans-diagnostic symptom may require targeting different neural circuits for perceptual attention or outcome-based attention depending on which type of attention is impaired in each neuro-psychiatric disorder.

The noradrenergic locus coeruleus (LC) is a crucial controller of brain and behavioral states. Activating LC neurons synchronously en masse by electrical or optogenetic stimulation promotes a stereotypical \"activated\" high-frequency cortical state. However, it has been recently reported that spontaneous LC cell-pairs have sparse yet structured time-averaged cross-correlations, which is unlike the high synchrony of en masse neuronal stimulation. This suggests the untested possibility that LC population activity may be made of distinct multi-cell ensembles each with unique temporal evolution of activity. We used non-negative matrix factorization (NMF) to analyze large populations of LC single units simultaneously recorded in the rat LC. Synthetic spike train simulations showed that NMF, unlike the traditional time-averaged pairwise correlations, detects both the precise neuronal composition and the activation time courses of each ensemble. NMF identified the existence of robust ensembles of spontaneously co-active LC neurons. Since LC neurons selectively project to specific forebrain regions, we hypothesized that individual LC ensembles produce different cortical states. To test this hypothesis, we triggered local field potentials (LFP) in cortical area 24a on the activation of distinct LC ensembles. We found four cortical states, each with different spectro-temporal LFP characteristics, that were robust across sessions and animals. While some LC ensembles triggered the activated state, others were associated with a beta oscillation-specific state or a reduced high frequency oscillation state. Thus - in contrast to the stereotypical \"activated\" brain state evoked by en masse LC stimulation - spontaneous activation of distinct LC ensembles can control a multitude of cortical states. Competing Interest Statement The authors have declared no competing interest. Footnotes * A new figure (Fig. 3) was added to demonstrate that NMF detects the composition of LC ensembles and their activation times, whereas graph-theoretic time-averaged pairwise correlations used in prior work does not. Additionally, the writing has been modified throughout to emphasise how the present study relates to prior work.

The lateral habenula (LHb) integrates aversive information to regulate motivated behaviors. Despite recent advances in identifying neuronal diversity at the molecular level, in vivo electrophysiological diversity of LHb neurons remains poorly understood. Understanding this diversity is essential for deciphering how information is processed in the LHb. To address this gap, we conducted in vivo electrophysiological recordings in mice and applied unsupervised clustering algorithm to analyze firing patterns. This analysis identified four distinct spontaneous firing patterns of LHb neurons, which were consistent across both anesthetized and awake states. To determine whether these firing patterns correlate with function, we recorded neuronal responses to foot shock stimulation in anesthetized mice and monitored spontaneous behavior in awake mice. We found that low-firing, bursting neurons were preferentially modulated by foot shocks in anesthetized mice and also tracked behavioral states in awake mice. Collectively, our findings indicate significant electrophysiological diversity among LHb neurons, which is associated with their modulation by aversive stimuli and behavioral state.