Correlation between cortical state and locus coeruleus activity: Implications for sensory coding in rat barrel cortex

Cortical state modulates the background activity of cortical neurons, and their evoked response to sensory stimulation. Multiple mechanisms are involved in switching between cortical states including various neuromodulatory systems. Locus Coeruleus (LC) is one of the major neuromodulatory nuclei in the brainstem with widespread projections throughout the brain and modulates the activity of cells and networks. Here, we quantified the link between the LC spontaneous activity, cortical state and sensory processing in the rat vibrissal somatosensory “barrel” cortex (BC). We simultaneously recorded unit activity from LC and BC along with prefrontal electroencephalogram (EEG) while presenting brief whisker deflections under urethane anesthesia. The ratio of low to high frequency components of EEG (referred to as the L/H ratio) was employed to identify cortical state. We found that the spontaneous activity of LC units exhibited a negative correlation with the L/H ratio. Cross-correlation analysis revealed that changes in LC firing preceded changes in the cortical state: the correlation of the LC firing profile with the L/H ratio was maximal at an average lag of −1.2 s. We further quantified BC neuronal responses to whisker stimulation during the synchronized and desynchronized states. In the desynchronized state, BC neurons showed lower stimulus detection threshold, higher response fidelity, and shorter response latency. The most prominent change was observed in the late phase of BC evoked activity (100–400 ms post stimulus onset): almost every BC unit exhibited a greater late response during the desynchronized state. Categorization of the BC evoked responses based on LC activity (into high and low LC discharge rates) resulted in highly similar response profiles compared to categorization based on the cortical state (low and high L/H ratios). These findings provide evidence for the involvement of the LC neuromodulatory system in desynchronization of cortical state and the consequent enhancement of sensory coding efficiency

Dopamine and Noradrenaline in the Brain; Overlapping or Dissociate Functions?

Dopamine and noradrenaline are crucial neuromodulators controlling brain states, vigilance, action, reward, learning, and memory processes. Ventral tegmental area (VTA) and Locus Coeruleus (LC) are canonically described as the main sources of dopamine (DA) and noradrenaline (NA) with dissociate functions. A comparison of diverse studies shows that these neuromodulators largely overlap in multiple domains such as shared biosynthetic pathway and co-release from the LC terminals, convergent innervations, non-specificity of receptors and transporters, and shared intracellular signaling pathways. DA-NA interactions are mainly studied in prefrontal cortex and hippocampus, yet it can be extended to the whole brain given the diversity of catecholamine innervations. LC can simultaneously broadcast both dopamine and noradrenaline across the brain. Here, we briefly review the molecular, cellular, and physiological overlaps between DA and NA systems and point to their functional implications. We suggest that DA and NA may function in parallel to facilitate learning and maintain the states required for normal cognitive processes. Various signaling modules of NA and DA have been targeted for developing of therapeutics. Understanding overlaps of the two systems is crucial for more effective interventions in a range of neuropsychiatric conditions

Er81 transcription factor fine-tunes striatal cholinergic interneuron activity and drives habit formation

The molecular mechanisms tuning cholinergic interneuron (CIN) activity, although crucial for striatal function and behavior, remain largely unexplored. Previous studies report that the Etv1/Er81 transcription factor is vital for regulating neuronal maturation and activity. While Er81 is known to be expressed in the striatum during development, its specific role in defining CIN properties and the resulting consequences on striatal function is unknown. We report here that Er81 is expressed in CINs and its specific ablation leads to prominent changes in their molecular, morphologic, and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further reveal that Er81 expression is required for normal CIN pause and time-locked responses to sensorimotor inputs in awake mice. Overall, this study uncovers a new cell type-specific control of CIN function in the striatum which drives habit formation in adult male mice

High-velocity stimulation evokes "dense" population response in layer 2/3 vibrissal cortex

Supra-granular layers of sensory cortex are known to exhibit sparse firing. In rodent vibrissal cortex, a small fraction of neurons in layer 2 and 3 (L2/3) respond to whisker stimulation. Here, we combined whole-cell recording and two-photon imaging in anesthetized mice and quantified the synaptic response and spiking profile of L2/3 neurons. Previous literature has shown that neurons across layers of vibrissal cortex are tuned to the velocity of whisker movement. We therefore used a broad range of stimuli that included the standard range of velocities (0-1.2 degree/ms) and extended to a "sharp" high-velocity deflection (3.8 degree/ms). Consistent with previous literature, whole-cell recording revealed a sparse response to the standard range of velocities: although all recorded cells showed tuning to velocity in their postsynaptic potentials, only a small fraction produced stimulus-evoked spikes. In contrast, the sharp stimulus evoked reliable spiking in the majority of neurons. The action-potential threshold of spikes evoked by the sharp stimulus was significantly lower than that of the spontaneous spikes. Juxta-cellular recordings confirmed that application of sharp stimulus to single or multiple whiskers produced temporally precise spiking with minimal trial-to-trial spike-count variability (Fano factors equal or close to the theoretical minimum). Two-photon imaging further confirmed that most neurons that were not responsive to the standard deflections responded to the sharp stimulus. Altogether, our results indicate that sparseness in L2/3 cortex depends on the choice of stimulus: strong single- or multi-whisker stimulation can induce the transition from sparse to "dense" population response.This work was supported by the Australian Research Council (ARC) Discovery Project DP130101364, Future Fellowship FT20100357, and the ARC Centre of Excellence for Integrative Brain Function CE14010000

Diverse tuning underlies sparse activity in layer 2/3 vibrissal cortex of awake mice

It is widely reported that superficial layers of the somatosensory cortex exhibit sparse firing. This sparseness could reflect weak feedforward sensory inputs that are not sufficient to generate action potentials in these layers. Alternatively, sparseness might reflect tuning to unknown or higher‐level complex features that are not fully explored in the stimulus space. Here, we examined these hypotheses by applying a range of vibrotactile and manual vibrissal stimuli in awake, head‐fixed mice while performing loose‐seal cell‐attached recordings from the vibrissal primary somatosensory (vS1) cortex. A high‐velocity stimulus delivered by a piezo‐electric actuator evoked activity in a small fraction of regular spiking supragranular neurons (23%) in the awake condition. However, a majority of the supragranular regular spiking neurons (84%) were driven by manual stimulation of whiskers. Our results suggest that most neurons in the superficial layers of vS1 cortex contribute to coding in the awake condition when neurons may encounter their preferred feature(s) during whisker–object interactions.This work was supported by a National Health and Medical Research Council (NHMRC; Australia) Project grant (1124411), an Australian Research Council (ARC) Discovery Projects grant (DP170100908), and by an ARC Centre of Excellence for Integrative Brain Function grant (CE140100007)