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...

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 ...

Amacrine cells, inhibitory interneurons of the retina, feature synaptic inputs and outputs in close proximity throughout their dendritic trees, making them notable exceptions to prototypical somato-dendritic integration with output transmitted via axonal action potentials. The extent of dendritic compartmentalization in amacrine cells with widely differing dendritic tree morphology, however, is largely unexplored. Combining compartmental modeling, dendritic Ca2+ imaging, targeted microiontophoresis and multielectrode patch-clamp recording (voltage and current clamp, capacitance measurement of exocytosis), we investigated integration in the AII amacrine cell, a narrow-field electrically coupled interneuron that participates in multiple, distinct microcircuits. Physiological experiments were performed with in vitro slices prepared from retinas of both male and female rats. We found that the morphology of the AII enables simultaneous local and global integration of inputs targeted to different dendritic regio...

Tau protein accumulation drives toxicity in several neurodegenerative disorders. To better understand the pathways regulating tau homeostasis in disease, we investigated the role of ubiquilins (UBQLNs)—a class of proteins linked to ubiquitin-mediated protein quality control (PQC) and various neurodegenerative diseases—in regulating tau. Cell-based assays identified UBQLN2 as the primary brain-expressed UBQLN to regulate tau. UBQLN2 efficiently lowered wild-type tau levels regardless of aggregation, suggesting that UBQLN2 interacts with and regulates tau protein under normal conditions or early in disease. Moreover, UBQLN2 itself proved to be prone to accumulation as insoluble protein in male and female tau transgenic mice and the human tauopathy progressive supranuclear palsy. Genetic manipulation of UBQLN2 in a tauopathy mouse model demonstrated that a physiological UBQLN2 balance is required for tau homeostasis. UBQLN2 overexpression exacerbated phosphorylated tau pathology and toxicity in mice expressin...

Episodic memory declines with advancing adult age. This decline is particularly pronounced when associations between items and their contexts need to be formed. According to theories of neural communication, the precise coupling of gamma power to the phase of the theta rhythm supports associative memory formation. To investigate whether age differences in associative memory are related to compromised theta-gamma coupling, we took EEG recordings during the encoding phase of an item-context association task. Fifty-eight younger (33 females) and 55 older (24 females) adults studied pictures of objects superimposed on background scenes. In a recognition test, objects were presented on old or new backgrounds, and participants responded if they had seen (1) the object and (2) the object/scene pair. Theta-gamma coupling supported pair memory formation in both age groups. Whereas pair memory was associated with coupling closer to the peak of the theta rhythm, item-only memory was associated with a deviation in pha...