Abnormal Ca2+ Signals in Reactive Astrocytes as a Common Cause of Brain Diseases

In pathological brain conditions, glial cells become reactive and show a variety of responses. We examined Ca2+ signals in pathological brains and found that reactive astrocytes share abnormal Ca2+ signals, even in different types of diseases. In a neuropathic pain model, astrocytes in the primary sensory cortex became reactive and showed frequent Ca2+ signals, resulting in the production of synaptogenic molecules, which led to misconnections of tactile and pain networks in the sensory cortex, thus causing neuropathic pain. In an epileptogenic model, hippocampal astrocytes also became reactive and showed frequent Ca2+ signals. In an Alexander disease (AxD) model, hGFAP-R239H knock-in mice showed accumulation of Rosenthal fibers, a typical pathological marker of AxD, and excessively large Ca2+ signals. Because the abnormal astrocytic Ca2+ signals observed in the above three disease models are dependent on type II inositol 1,4,5-trisphosphate receptors (IP3RII), we reanalyzed these pathological events using IP3RII-deficient mice and found that all abnormal Ca2+ signals and pathologies were markedly reduced. These findings indicate that abnormal Ca2+ signaling is not only a consequence but may also be greatly involved in the cause of these diseases. Abnormal Ca2+ signals in reactive astrocytes may represent an underlying pathology common to multiple diseases.

Learning enhances encoding of time and temporal surprise in primary sensory cortex

Primary sensory cortex has long been believed to play a straightforward role in the initial processing of sensory information. Yet, the superficial layers of cortex overall are sparsely active, even during sensory stimulation; moreover, cortical activity is influenced by other modalities, task context, reward, and behavioral state. Our study demonstrates that reinforcement learning dramatically alters representations among longitudinally imaged neurons in superficial layers of mouse primary somatosensory cortex. Learning an object detection task recruits previously unresponsive neurons, enlarging the neuronal population sensitive to touch and behavioral choice. In contrast, cortical responses decrease upon repeated exposure to unrewarded stimuli. Moreover, training improved population encoding of the passage of time, and unexpected deviations in trial timing elicited even stronger responses than touch did. In conclusion, the superficial layers of sensory cortex exhibit a high degree of learning-dependent plasticity and are strongly modulated by non-sensory but behaviorally-relevant features, such as timing and surprise.

Sensory cortical dynamics during optical microstimulation training

Primary sensory cortex is a key locus of plasticity during learning. Exposure to novel stimuli often alters cortical activity, but isolating cortex-specific dynamics is challenging due to extensive pre-cortical processing. Here, we employ optical microstimulation of pyramidal neurons in layer (L) 2/3 of mouse primary vibrissal somatosensory cortex (vS1) to study cortical dynamics as mice learn to discriminate microstimulation intensity. Tracking activity over weeks using two-photon calcium imaging, we observe a rapid sparsification of the photoresponsive population, with the most responsive neurons exhibiting the largest declines in responsiveness. Following sparsification, the photoresponsive population attains a stable rate of neuronal turnover. At the same time, the photoresponsive population increasingly overlaps with populations encoding whisker movement and touch. Finally, we find that mice with larger declines in responsiveness learn the task more slowly than mice with smaller declines. Our results reveal that microstimulation-evoked cortical activity undergoes extensive reorganization during task learning and that the dynamics of this reorganization impact perception.

The effects of locomotion on sensory-evoked haemodynamic responses in the cortex of awake mice

Investigating neurovascular coupling in awake rodents is becoming ever more popular due, in part, to our increasing knowledge of the profound impacts that anaesthesia can have upon brain physiology. Although awake imaging brings with it many advantages, we still do not fully understand how voluntary locomotion during imaging affects sensory-evoked haemodynamic responses. In this study we investigated how evoked haemodynamic responses can be affected by the amount and timing of locomotion. Using an awake imaging set up, we used 2D-Optical Imaging Spectroscopy (2D-OIS) to measure changes in cerebral haemodynamics within the sensory cortex of the brain during either 2s whisker stimulation or spontaneous (no whisker stimulation) experiments, whilst animals could walk on a spherical treadmill. We show that locomotion alters haemodynamic responses. The amount and timing of locomotion relative to whisker stimulation is important, and can significantly impact sensory-evoked haemodynamic responses. If locomotion occurred before or during whisker stimulation, the amplitude of the stimulus-evoked haemodynamic response was significantly altered. Therefore, monitoring of locomotion during awake imaging is necessary to ensure that conclusions based on comparisons of evoked haemodynamic responses (e.g., between control and disease groups) are not confounded by the effects of locomotion.

Endogenous recruitment of frontal-sensory circuits during visual discrimination

A long-range circuit linking anterior cingulate cortex (ACC) to primary visual cortex (V1) has been previously proposed to mediate visual selective attention in mice during visually guided behaviour. Here we used in vivo two-photon functional imaging to measure endogenous activity of ACC neurons projecting to layer 1 of V1 (ACC-V1axons) in mice either passively viewing stimuli or performing a go/no-go visually guided task. We observed that while ACC-V1axons were recruited under these conditions, this was not linked to enhancement of neural or behavioural measures of sensory coding. Instead, ACC-V1axon activity was observed to be associated with licking behaviour, modulated by reward, and biased towards task relevant sensory cortex.

VIP interneurons in mouse whisker S1 exhibit sensory and action-related signals during goal-directed behavior

Vasoactive intestinal peptide-expressing (VIP) interneurons, which constitute 10-15% of the cortical inhibitory neuron population, have emerged as an important cell type for regulating excitatory cell activity based on behavioral state. VIP cells in sensory cortex are potently engaged by neuromodulatory and motor inputs during active exploratory behaviors like locomotion and whisking, which in turn promote pyramidal cell firing via disinhibition. Such state-dependent modulation of activity by VIP cells in sensory cortex has been studied widely in recent years. However, the function of VIP cells during goal-directed behavior is less well understood. It is not clear how task-related events like sensory stimuli, motor actions, or reward activate VIP cells in sensory cortex since there is often temporal overlap in the occurrence of these events. We developed a Go/NoGo whisker touch detection task which incorporates a post-stimulus delay period to separate sensory-driven activity from action- or reward-related activity during behavior. We used 2-photon calcium imaging to measure task-related signals of L2/3 VIP neurons in S1 of behaving mice. We report for the first time that VIP cells in mouse whisker S1 are activated by both whisker stimuli and goal-directed licking. Whisker- and lick-related signals were spatially organized in relation to anatomical columns in S1. Sensory responses of VIP cells were tuned to specific whiskers, whether or not they also displayed lick-related activity.

Awake perception is associated with dedicated neuronal assemblies in cerebral cortex

Neural activity in sensory cortex combines stimulus responses and ongoing activity, but it remains unclear whether they reflect the same underlying dynamics or separate processes. Here we show that during wakefulness, the neuronal assemblies evoked by sounds in the auditory cortex and thalamus are specific to the stimulus and distinct from the assemblies observed in ongoing activity. In contrast, during anesthesia, evoked assemblies are indistinguishable from ongoing assemblies in cortex, while they remain distinct in the thalamus. A strong remapping of sensory responses accompanies this dynamical state change produced by anesthesia. Together, these results show that the awake cortex engages dedicated neuronal assemblies in response to sensory inputs, which we suggest is a network correlate of sensory perception.One-Sentence SummarySensory responses in the awake cortex engage specific neuronal assemblies that disappear under anesthesia.

Neural evidence for the successor representation in choice evaluation

Evaluating choices in multi-step tasks is thought to involve mentally simulating trajectories. Recent theories propose that the brain simplifies these laborious computations using temporal abstraction: storing actions’ consequences, collapsed over multiple timesteps (the Successor Representation; SR). Although predictive neural representations and, separately, behavioral errors (“slips of action”) consistent with this mechanism have been reported, it is unknown whether these neural representations support choices in a manner consistent with the SR. We addressed this question by using fMRI to measure predictive representations in a setting where the SR implies specific errors in multi-step expectancies and corresponding behavioral errors. By decoding measures of state predictions from sensory cortex during choice evaluation, we identified evidence that behavioral errors predicted by the SR are accompanied by predictive representations of upcoming task states reflecting SR predicted erroneous multi-step expectancies. These results provide neural evidence for the SR in choice evaluation and contribute toward a mechanistic understanding of flexible and inflexible decision making.

Pattern separation and tuning shift in human sensory cortex underlie fear memory

ABSTRACTAnimal research has recognized the role of the sensory cortex in fear memory and two key underlying mechanisms—pattern separation and tuning shift. We interrogated these mechanisms in the human sensory cortex in an olfactory differential conditioning study with a delayed (9-day) retention test. Combining affective appraisal and olfactory psychophysics with functional magnetic resonance imaging (fMRI) multivoxel pattern analysis and voxel-based tuning analysis over a linear odor-morphing continuum, we confirmed affective and perceptual learning and memory and demonstrated associative plasticity in the human olfactory (piriform) cortex. Specifically, the piriform cortex exhibited immediate and lasting enhancement in pattern separation (between the conditioned stimuli/CS and neighboring non-CS) and late-onset yet lasting tuning shift towards the CS, especially in anxious individuals. These findings highlight an evolutionarily conserved sensory cortical system of fear memory, which can underpin sensory encoding of fear/threat and confer a sensory mechanism to the neuropathophysiology of anxiety.