Autonomic parasympathetic preganglionic neurons (PGN) drive contraction of the bladder during micturition but remain quiescent during bladder filling. This quiescence is postulated to be due to recurrent inhibition of PGN by fast-firing adjoining interneurons. Here, we defined four distinct neuronal types within lamina VII of the lumbosacral spinal cord, where PGN are situated, by combining whole cell patch clamp recordings with k-means clustering of a range of electrophysiological parameters. Additional morphological analysis separated these neuronal classes into parasympathetic preganglionic populations (PGN) and a fast firing interneuronal population. Kv3 channels are voltage-gated potassium channels (Kv) that allow fast and precise firing of neurons. We found that blockade of Kv3 channels by tetraethylammonium (TEA) reduced neuronal firing frequency and isolated high-voltage-activated Kv currents in the fast-firing population but had no effect in PGN populations. Furthermore, Kv3 blockade potentiated t...

The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra™), a novel FDA approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behaviour and pronociceptive signalling in dorsal root ganglia (DRG) and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, increased PI3K/Akt-signalling in small-diameter DRG neurons and an increase of CD68+ cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH follo...

Value-based decision-making is often studied in a static context, where participants decide which option to select from those currently available. However, everyday life often involves an additional dimension: deciding when to select to maximise reward. Recent evidence suggests that agents track the latent reward of an option, updating changes in their latent reward estimate, to achieve appropriate selection timing ( latent reward tracking ). However, this strategy can be difficult to distinguish from one in which the optimal selection time is estimated in advance, allowing an agent to wait a pre-determined amount of time before selecting, without needing to monitor an option’s latent reward ( distance-to-goal tracking ). Here we show that these strategies can in principle be dissociated. Human brain activity was recorded using electroencephalography (EEG) while female and male participants performed a novel decision task. Participants were shown an option and decided when to select it, as its latent rewar...

The brain continues to respond selectively to environmental stimuli during sleep. However, the functional role of such responses, and whether they reflect information processing or rather sensory inhibition is not fully understood. Here, we present 17 human sleepers (14 females) with their own name and two unfamiliar first names, spoken by either a familiar voice (FV) or an unfamiliar voice (UFV), while recording polysomnography during a full night’s sleep. We detect K-complexes, sleep spindles, and micro-arousals, and assess event-related, and frequency responses as well as inter-trial phase synchronization to the different stimuli presented during non-rapid eye movement (NREM) sleep. We show that UFVs evoke more K-complexes and micro-arousals than FVs. When both stimuli evoke a K-complex, we observe larger evoked potentials, more precise time-locking of brain responses in the delta band (1-4 Hz), and stronger activity in the high frequency (>16Hz) range, in response to UFVs relative to FVs. Crucially, ...

Repeated pairing of a drug with a neutral stimulus, such as a cue or context, leads to the attribution of the drug’s reinforcing properties to that stimulus, and exposure to that stimulus in the absence of the drug can elicit drug-seeking. A principal role for the NAc in the response to drug-associated stimuli has been well documented. Direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity toward the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs, remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement is unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to begin t...

Cortical layer 1 (L1) contains a diverse population of interneurons which can modulate processing in superficial cortical layers, but the intracortical sources of synaptic input to these neurons, and how these inputs change over development and with sensory experience, is unknown. We here investigated the changing intracortical connectivity to L1 in the primary auditory cortex (A1) of mice of both sexes in in vitro slices across development using laser-scanning photostimulation. Before postnatal day (P)10, L1 cells receive excitatory input from within L1, L2/3, L4, and L5/6 as well as from subplate. Excitatory inputs from all layers increase, especially from L4, and peak during P10-P16, around the peak of the critical period for tonotopy. Inhibitory inputs followed a similar pattern. Functional circuit diversity in L1 emerges after P16. In adults, L1 neurons receive ascending inputs from L2/3 and L5/6, but only few inputs from L4. The transient hyperconnectivity from deep layers but not L2/3 is absent in d...

Adult neural stem cells (NSCs) reside in two distinct niches in the mammalian brain, the ventricular-subventricular zone (V-SVZ) of the forebrain lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. They are thought to be molecularly distinct since V-SVZ NSCs produce inhibitory olfactory bulb (OB) interneurons and SGZ NSCs excitatory dentate granule neurons. Here, we have asked whether this is so by directly comparing V-SVZ and SGZ NSCs from embryogenesis to adulthood using single-cell transcriptional data. We show that the embryonic radial glial precursor (RP) parents of these two NSC populations are very similar, but differentially express a small cohort of genes involved in glutamatergic versus GABAergic neurogenesis. These different RPs then undergo a similar gradual transition to a dormant adult NSC state over the first three postnatal weeks. This dormancy state involves transcriptional shutdown of genes that maintain an active, proliferative, prodifferentiation state an...

Protein hyper-deimination and deficiency of lyso-phospholipids (LPC 18:1) has been associated with the pathology of demyelinating disease in both humans and mice. We uncovered interesting biology of LPC 18:1, in which LPC 18:1 induced optic nerve function restoration through oligodendrocyte maturation and remyelination in mouse model systems. Our in vitro studies show LPC 18:1 protection against neuron-ectopic hyper-deimination and stimulation of oligodendrocyte maturation, while in vivo investigations recorded optic nerve function improvement following optic nerve injections of LPC 18:1, in contrast to LPC 18:0. Thus just a change in a single bond renders a dramatic alternation in biological function. The incorporation of isobaric C13-histidine in newly synthesized myelin proteins and quantitative proteome shifts are consistent with remyelination underlying restoration in optic nerve function. These results suggest that exogenous LPC 18:1 may provide a therapeutic avenue for stemming vision loss in demyel...

A surprising finding of recent studies in mouse is the dominance of widespread movement-related activity throughout the brain, including in early sensory areas. In awake subjects, failing to account for movement risks misattributing movement-related activity to other (e.g., sensory or cognitive) processes. In this article, we 1) review task designs for separating task-related and movement-related activity, 2) review three ‘case studies’ in which not considering movement would have resulted in critically different interpretations of neuronal function, and 3) discuss functional couplings that may prevent us from ever fully isolating sensory, motor, and cognitive-related activity. Our main thesis is that neural signals related to movement are ubiquitous, and therefore ought to be considered first and foremost when attempting to correlate neuronal activity with task-related processes.

Trigeminal neurons convey somatosensory information from craniofacial tissues. In mouse brain, ascending projections from medullary trigeminal neurons arrive at taste neurons in the parabrachial nucleus, suggesting that taste neurons participate in somatosensory processing. However, the cell types that support this convergence were undefined. Using Cre-directed optogenetics and in vivo neurophysiology in anesthetized mice of both sexes, here we studied whether TRPV1-lineage nociceptive and thermosensory fibers are primary neurons that drive trigeminal circuits reaching parabrachial taste cells. We monitored spiking activity in individual parabrachial neurons during photoexcitation of the terminals of TRPV1-lineage fibers arriving at the dorsal trigeminal nucleus caudalis, which relays orofacial somatosensory messages to the parabrachial area. We also recorded parabrachial neural responses to oral delivery of taste, chemesthetic, and thermal stimuli. We found that optical excitation of TRPV1-lineage fibers ...