Neuropathic pain (NP) is one of the most common and debilitating comorbidities of spinal cord injury (SCI). Current therapies are often ineffective due in part to an incomplete understanding of underlying pathogenic mechanisms. In particular, it remains unclear how SCI leads to dysfunction in the excitability of nociceptive circuitry. The immediate early gene c-Fos has long been used in pain processing locations as a marker of neuronal activation. We employed a mouse reporter line with fos-promoter driven Cre-recombinase to define neuronal activity changes in relevant pain circuitry locations following C5/6 contusion (using both females and males), a SCI model that results in multiple forms of persistent NP-related behavior. SCI significantly increased activation of cervical dorsal horn (DH) projection neurons, as well as induced a selective reduction in the activation of a specific DH projection neuron subpopulation that innervates the periaqueductal gray (PAG), an important brain region involved in desce...

Opioid tolerance (OT) leads to dose escalation and serious side effects, including opioid-induced hyperalgesia (OIH). We sought to better understand the mechanisms underlying this event in the gastrointestinal tract. Chronic in vivo administration of morphine by intraperitoneal (i.p.) injection in male C57BL/6 mice evoked tolerance and evidence of OIH in an assay of colonic afferent nerve mechanosensitivity; this was inhibited by the δ-opioid receptor (DOPr) antagonist naltrindole when i.p. injected previous morphine administration. Patch clamp studies of dorsal root ganglia (DRG) neurons following overnight incubation with high concentrations of morphine, the µ-opioid receptors (MOPr) agonist DAMGO or the DOPr agonist DADLE evoked hyperexcitability. The pronociceptive actions of these opioids were blocked by the DOPr antagonist SDM25N but not the MOPr antagonist CTOP. The hyperexcitability induced by DAMGO was reversed after a 1 hr washout but reapplication of low concentrations of DAMGO or DADLE restored...

Traumatic spinal cord injury (SCI) is a leading cause of permanent neurological disabilities in young adults. Functional impairments after SCI are substantially attributed to the progressive neurodegeneration. However, regeneration of spinal specific neurons and circuit re-assembly remain challenging in the dysregulated milieu of SCI due to impaired neurogenesis and neuronal maturation by neural precursor cells (NPCs) spontaneously or in cell-based strategies. The extrinsic mechanisms that regulate neuronal differentiation and synaptogenesis in SCI are poorly understood. Here, we perform extensive in vitro and in vivo studies to unravel that SCI-induced upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) impedes neurogenesis of NPCs through co-activation of two receptor protein tyrosine phosphatases, LAR and PTPσ. In adult female rats with SCI, systemic co-inhibition of LAR and PTPσ promotes regeneration of motoneurons and spinal interneurons by engrafted human directly reprogrammed caudalized...

Anti-NMDAR encephalitis is a severe neuropsychiatric disorder associated with autoantibodies against NMDA receptors, which cause a variety of symptoms from prominent psychiatric and cognitive manifestations to seizures and autonomic instability. Previous studies mainly focused on hippocampal effects of these autoantibodies, helping to explain mechanistic causes for cognitive impairment. However, antibodies’ effects on higher cortical network function, where they could contribute to psychosis and/or seizures, have not until now been explored in detail. Here, we employed a patient-derived monoclonal antibody targeting the NR1 subunit of NMDAR and tested its effects on in vitro cultures of rodent cortical neurons, using imaging and electrophysiological techniques. We report that this hNR1 antibody drives cortical networks to a hyper-excitable state and disrupts mechanisms stabilizing network activity such as Npas4 signaling. Network hyperactivity is in part a result of a reduced synaptic output of inhibitory ...

Auditory cortex (ACX) neurons are sensitive to spectro-temporal sound patterns and violations in patterns induced by rare stimuli embedded within streams of sounds. We investigate the auditory cortical representation of repeated presentations of sequences of sounds with standard stimuli (common) with an embedded deviant (rare) stimulus in two conditions – Periodic (Fixed deviant position) or Random (Random deviant position). We used extracellular single-unit and 2-photon Ca2+ imaging recordings in Layer 2/3 neurons of the mouse (mus musculus) ACX of either sex. Population single unit average responses increased over repetitions in the Random-condition and were suppressed or did not change in the Periodic-condition, showing general irregularity preference. A subset of neurons showed the opposite behaviour, indicating regularity preference. Furthermore, pairwise noise-correlations were higher in the Random-condition than in the Periodic-condition, suggesting a role of recurrent connections in the observed di...

The control of contraction strength is a key part of movement control. In primates, both corticospinal and reticulospinal cells provide input to motoneurons. Corticospinal discharge is known to correlate with force, but there are no previous reports of how reticular formation (RF) activity modulates with different contractions. Here we trained two female macaque monkeys (body weight 5.9-6.9kg) to pull a handle which could be loaded with 0.5-6kg weights, and recorded from identified pyramidal tract neurons (PTNs) in primary motor cortex and RF cells during task performance. Population-averaged firing rate increased monotonically with higher force for the RF, but showed a complex profile with little net modulation for PTNs. This reflected a more heterogeneous profile of rate modulation across the PTN population, leading to cancellation in the average. Linear discriminant analysis (LDA) classified the force based on the time course of rate modulation equally well for PTNs and RF cells. Peak firing rate had si...

Feedforward and feedback pathways interact in specific dendritic domains to enable cognitive functions such as predictive processing and learning. Based on axonal projections, hierarchically lower areas are thought to form synapses primarily on dendrites in middle cortical layers, while higher-order areas are posited to target dendrites in layer 1 and in deep layers. However, the extent to which functional synapses form in regions of axo-dendritic overlap has not been extensively studied. Here, we use viral tracing in the secondary visual cortex of male mice to map brain-wide inputs to thick-tufted layer 5 pyramidal neurons. Furthermore, we provide a comprehensive map of input locations through subcellular optogenetic circuit mapping. We show that input pathways target distinct dendritic domains with far greater specificity than appears from their axonal branching, often deviating substantially from the canonical patterns. Common assumptions regarding the dendrite-level interaction of feedforward and feedb...

This paper is about neural mechanisms of direction selectivity (DS) in Macaque primary visual cortex, V1. We present data (on male macaque) showing strong DS in a majority of simple cells in V1 layer 4Cα, the cortical layer that receives direct afferent input from the Magnocellular division of the Lateral Geniculate Nucleus (LGN). Magnocellular LGN cells are not direction-selective. To understand the mechanisms of DS, we built a large-scale, recurrent model of spiking neurons called DSV1. Like its predecessors, DSV1 reproduces many visual response properties of V1 cells including orientation selectivity. Two important new features of DSV1 are (a) DS is initiated by small, consistent dynamic differences in the visual responses of OFF and ON Magnocellular LGN cells, and (b) DS in the responses of most model simple cells is increased over those of their feedforward inputs; this increase is achieved through dynamic interaction of feedforward and intra-cortical synaptic currents without the use of intra-cortica...

ClC-3, ClC-4, and ClC-5 are electrogenic chloride/proton exchangers that can be found in endosomal compartments of mammalian cells. Although the association with genetic diseases and the severe phenotype of knockout animals illustrate their physiological importance, the cellular functions of these proteins have remained insufficiently understood. We here study the role of two Clcn3 splice variants, ClC-3b and ClC-3c, in granular exocytosis and catecholamine accumulation of adrenal chromaffin cells using a combination of high-resolution capacitance measurements, amperometry, protein expression/gene knock-out/down, rescue experiments, and confocal microscopy. We demonstrate that ClC-3c resides in immature as well as in mature secretory granules, where it regulates catecholamine accumulation and contributes to the establishment of the readily releasable pool of secretory vesicles. The lysosomal splice variant ClC-3b contributes to vesicle priming only with low efficiency and leaves the vesicular catecholamine...

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 maximize 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 predetermined 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 reward c...