Odours are transported by turbulent air currents, creating complex temporal fluctuations in odour concentration that provide a potentially informative stimulus dimension. Recently, we have shown that mice are able to discriminate odour stimuli based on their temporal structure, indicating that information contained in the temporal structure of odour plumes can be extracted by the mouse olfactory system. Here, using in vivo extra- and intracellular electrophysiological recordings, we show that mitral and tufted cells (M/TCs) of the male C57BL/6 mouse olfactory bulb can encode the dominant temporal frequencies present in odour stimuli up to at least 20 Hz. A substantial population of cell-odour pairs showed significant coupling of their subthreshold membrane potential with the odour stimulus at both 2Hz (29/70) and the supra-sniff frequency 20Hz (24/70). Furthermore, M/TCs show differential coupling of their membrane potential to odour concentration fluctuations with tufted cells coupling more strongly for t...

Traumatic brain injury (TBI) is associated with an increased risk of cognitive, psychiatric, and neurodegenerative complications that may develop after injury. Increased microglial reactivity following TBI may underlie chronic neuroinflammation, neuropathology, and exaggerated responses to immune challenges. Therefore, the goal of this study was to force turnover of trauma-associated microglia that develop after diffuse TBI and determine if this alleviated chronic inflammation, improved functional recovery and attenuated reduced immune reactivity to lipopolysaccharide (LPS) challenge. Male mice received a midline fluid percussion injury and 7 days later were subjected to a forced microglia turnover paradigm using CSF1R antagonism (PLX5622). At 30 days post injury (dpi), cortical gene expression, dendritic complexity, myelin content, neuronal connectivity, cognition, and immune reactivity were assessed. Myriad neuropathology-related genes were increased 30 dpi in the cortex, and 90% of these gene changes we...

Torpor is a naturally occurring, hypometabolic, hypothermic state engaged by a wide range of animals in response to imbalance between the supply and demand for nutrients. Recent work has identified some of the key neuronal populations involved in daily torpor induction in mice, in particular projections from the preoptic area of the hypothalamus (POA) to the dorsomedial hypothalamus (DMH). The DMH plays a role in thermoregulation, control of energy expenditure, and circadian rhythms, making it well positioned to contribute to the expression of torpor. We used activity dependent genetic TRAPing techniques to target DMH neurons that were active during natural torpor bouts in female mice. Chemogenetic reactivation of torpor-TRAPed DMH neurons in calorie-restricted mice promoted torpor, resulting in longer and deeper torpor bouts. Chemogenetic inhibition of torpor-TRAPed DMH neurons did not block torpor entry, suggesting a modulatory role for the DMH in the control of torpor. This work adds to the evidence tha...

Cortical GABAergic interneurons have been shown to fulfil important roles by inhibiting excitatory principal neurons. Recent transcriptomic studies have confirmed seminal discoveries that used anatomical and electrophysiological methods highlighting the existence of multiple different classes of GABAergic interneurons. Although some of these studies have emphasized that inter-regional differences may exist for a given class, the extent of such differences remains unknown. To address this problem, we used single-cell Patch-RNAseq to characterise neuropeptide Y (NPY)-positive GABAergic interneurons in superficial layers of the primary auditory cortex and in distal layers of area CA3 in mice. We found that more than 300 genes are differentially expressed in NPY-positive neurons between these two brain regions. For example, the AMPA receptor auxiliary subunit Shisa9/CKAMP44 and the 5HT2a receptor are significantly higher expressed in auditory NPY-positive neurons. These findings guided us to perform pharmacolo...

Understanding the long-term effects of stress on brain function is crucial for understanding the mechanisms of depression. The BALB/c mouse strain has high susceptibility to stress and is thus an effective model for depression. The long-term effects of repeated social defeat stress (SDS) on BALB/c mice, however, are not clear. Here we investigated the effects of repeated SDS in male BALB/c mice over the subsequent 2 weeks. Some defeated mice immediately exhibited social avoidance whereas anxiety-like behavior was only evident at later periods. Furthermore, defeated mice segregated into 2 groups based on the level of social avoidance, namely avoidant and non-avoidant mice. The characteristic of avoidance or non-avoidance in each individual was not fixed over the 2 weeks. In addition, we developed a semi-automated method for analyzing c-Fos expression in the mouse brain to investigate the effect of repeated SDS on brain activity more than 2 weeks after the end of the stress exposure. Following social interac...

How do people limit awareness of unwanted memories? When such memories intrude, a control process engages the right DLPFC (rDLPFC) to inhibit hippocampal activity and stop retrieval. It remains unknown how the need for control is detected, and whether control operates proactively to prevent unwelcome memories from being retrieved, or responds reactively, to counteract intrusions. We hypothesized that dorsal ACC (dACC) detects the emergence of an unwanted trace in awareness and transmits the need for inhibitory control to rDLPFC. During a memory suppression task, we measured in humans (both sexes) trial-by-trial variations in dACC’s theta power and N2 amplitude, two EEG markers thought to reflect the need for control. With simultaneous EEG-fMRI recordings, we tracked interactions between dACC, rDLPFC and hippocampus during suppression. We found a clear role of dACC in detecting the need for memory control and upregulating prefrontal inhibition. Importantly, we identified distinct early (350-400 ms) and late...

Alcohol use disorder (AUD) causes complex alterations in the brain that are poorly understood. The heterogeneity of drinking patterns and the high incidence of comorbid factors compromise mechanistic investigations in AUD patients. Here we used male Marchigian Sardinian alcohol-preferring (msP) rats, a well established animal model of chronic alcohol drinking, and a combination of longitudinal resting-state fMRI and manganese-enhanced MRI to provide objective measurements of brain connectivity and activity, respectively. We found that 1 month of chronic alcohol drinking changed the correlation between resting-state networks. The change was not homogeneous, resulting in the reorganization of pairwise interactions and a shift in the equilibrium of functional connections. We identified two fundamentally different forms of network reorganization. First is functional dedifferentiation, which is defined as a regional increase in neuronal activity and overall correlation, with a concomitant decrease in preferenti...

Nogo-66 receptors (NgR1-3) are glycosylphosphatidyl inositol-linked proteins that belong to the leucine-rich repeat superfamily. Through binding to myelin-associated inhibitors, NgRs contribute to the inhibition of axonal regeneration after spinal cord injury. Their role in limiting synaptic plasticity and axonal outgrowth in the adult CNS has been described previously, but not much is known about their role during the development of the nervous system. Here, we show that NgR1 and NgR3 mRNAs are expressed during spinal cord development of the chicken embryo. In particular, they are expressed in the dI1 subpopulation of commissural neurons during the time when their axons navigate toward and across the floorplate, the ventral midline of the spinal cord. To assess a potential role of NgR1 and NgR3 in axon guidance, we downregulated them using in ovo RNAi and analyzed the trajectory of commissural axons by tracing them in open-book preparations of spinal cords. Our results show that loss of either NgR1 or NgR...

Acetylcholine (ACh) is thought to control arousal, attention, and learning by slowly modulating cortical excitability and plasticity. Recent studies, however, discovered that cholinergic neurons emit precisely timed signals about the aversive outcome at millisecond precision. To investigate the functional relevance of such phasic cholinergic signaling, we manipulated and monitored cholinergic terminals in the mPFC while male mice associated a neutral conditioned stimulus (CS) with mildly aversive eyelid shock (US) over a short temporal gap. Optogenetic inhibition of cholinergic terminals during the US promoted the formation of the CS–US association. On the contrary, optogenetic excitation of cholinergic terminals during the US blocked the association formation. The bidirectional behavioral effects paralleled the corresponding change in the expression of an activity-regulated gene, c-Fos in the mPFC. In contrast, optogenetic inhibition of cholinergic terminals during the CS impaired associative learning, wh...

Nociceptive information is detected and transmitted by neurons in the dorsal root ganglion (DRG). Recently, single-cell RNA-sequencing has revealed the molecular profile of various cell types including fibroblasts in the DRG. However, the role of molecules in fibroblasts needs to be elucidated in nociceptive regulation. Here, we found that secreted modular calcium-binding protein 2 (SMOC2) was secreted by fibroblasts to become a component of basement membrane and envelop the unit consisting of DRG neurons and attached satellite glial cells (SGCs). Knockout of SMOC2 in both sexes of mice led to increased neuronal clusters and decreased mechanical threshold, but unchanged noxious thermal response. Knockdown of SMOC2 in the DRG phenocopied the behavioral performance by SMOC2 knockout in both sexes of mice. In vivo calcium imaging showed that SMOC2 knockout increased coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli, which was reversed by DRG injection of SMOC2. Importantly, ...