The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer's disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC–NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC–NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6- t...

The successful recognition of familiar persons is critical for social interactions. Despite extensive research on the neural representations of familiar faces, we know little about how such representations unfold as someone becomes familiar. In three EEG experiments on human participants of both sexes, we elucidated how representations of face familiarity and identity emerge from different qualities of familiarization: brief perceptual exposure (Experiment 1), extensive media familiarization (Experiment 2), and real-life personal familiarization (Experiment 3). Time-resolved representational similarity analysis revealed that familiarization quality has a profound impact on representations of face familiarity: they were strongly visible after personal familiarization, weaker after media familiarization, and absent after perceptual familiarization. Across all experiments, we found no enhancement of face identity representation, suggesting that familiarity and identity representations emerge independently dur...

Signal correlation ( r s) is commonly defined as the correlation between the tuning curves of two neurons and is widely used as a metric of tuning similarity. It is fundamental to how populations of neurons represent stimuli and has been central to many studies of neural coding. Yet the classic estimate, Pearson's correlation coefficient, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mrow><mml:msub><mml:mover accent="true"><mml:mi>r</mml:mi><mml:mo>̂</mml:mo></mml:mover><mml:mi mathvariant="normal">s</mml:mi></mml:msub></mml:mrow></mml:math>, between the average responses of two neurons to a set of stimuli suffers from confounding biases. The estimate <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline"><mml:mrow><mml:msub><mml:mover accent="true"><mml:mi>r</mml:mi><mml:mo>̂</mml:mo></mml:mover><mml:mi mathvariant="normal">s</mml:mi></mml:msub></mml:mrow></mml:math> can be downwardly biased by trial-to-trial variability and also upwardly biased by trial...

Lower urinary tract or voiding disorders are prevalent across all ages and affect over 40% of adults over 40 years old leading to decreased quality of life and high healthcare costs. The pontine micturition center (PMC; ie, Barrington’s nucleus) contains a large population of neurons that localize the stress-related neuropeptide, corticotropin-releasing hormone (CRH) and project to neurons in the spinal cord to regulate micturition. How the PMC and CRH-expressing neurons in the PMC control volitional micturition is of critical importance for human voiding disorders. To investigate the specific role of CRH in the PMC, neurons in the PMC expressing CRH were optogenetically activated during in vivo cystometry in unanesthetized mice of either sex. Optogenetic activation of CRH-PMC neurons led to increased intermicturition interval and voided volume, similar to the altered voiding phenotype produced by social stress. Female mice showed a significantly more pronounced phenotype change compared with male mice. Th...

The human brain extracts statistical regularities embedded in real-world scenes to sift through the complexity stemming from changing dynamics and entwined uncertainty along multiple perceptual dimensions (e.g., pitch, timbre, location). While there is evidence that sensory dynamics along different auditory dimensions are tracked independently by separate cortical networks, how these statistics are integrated to give rise to unified objects remains unknown, particularly in dynamic scenes that lack conspicuous coupling between features. Using tone sequences with stochastic regularities along spectral and spatial dimensions, this study examines behavioral and electrophysiological responses from human listeners (male and female) to changing statistics in auditory sequences, and employs a computational model of predictive Bayesian inference to formulate multiple hypotheses for statistical integration across features. Neural responses reveal multiplexed brain responses reflecting both local statistics along ind...

Neural activity at the large-scale population level has been suggested to be consistent with a sequence of brief, quasi-stable spatial patterns. These “microstates” and their temporal dynamics have been linked to myriad cognitive functions and brain diseases. Most of this research has been performed using EEG, leaving many questions unaddressed, such as the existence, dynamics, and behavioral relevance of microstates at the level of local field potentials (LFP). Here, we adapted the standard EEG microstate analysis to triple-area LFP recordings from 192 electrodes in rats, in order to investigate the mesoscopic dynamics of neural microstates within and across brain regions during novelty exploration. We performed simultaneous recordings from the prefrontal cortex (PFC), striatum (STR), and ventral tegmental area (VTA) in male rats during awake behavior (object novelty and exploration). We found that the LFP data can be accounted for by multiple, recurring, microstates that were stable for ∼60-100 ms. The ...

Distributed population codes are ubiquitous in the brain and pose a challenge to downstream neurons that must learn an appropriate readout. Here we explore the possibility that this learning problem is simplified through inductive biases implemented by stimulus-independent noise correlations that constrain learning to task-relevant dimensions. We test this idea in a set of neural networks that learn to perform a perceptual discrimination task. Correlations among similarly tuned units were manipulated independently of overall population signal-to-noise ratio in order to test how the format of stored information affects learning. Higher noise correlations among similarly tuned units led to faster and more robust learning, favoring homogenous weights assigned to neurons within a functionally similar pool, and could emerge through Hebbian learning. When multiple discriminations were learned simultaneously, noise correlations across relevant feature dimensions sped learning whereas those across irrelevant featu...

Epigenetic modifiers are increasingly being investigated as potential therapeutics to modify and overcome disease phenotypes. Diseases of the nervous system present a particular problem as neurons are postmitotic and demonstrate relatively stable gene expression patterns and chromatin organization. We have explored the ability of epigenetic modifiers to prevent degeneration of rod photoreceptors in a mouse model of retinitis pigmentosa (RP), using rd10 mice of both sexes. The histone modification eraser enzymes LSD1 and HDAC1 are known to have dramatic effects on the development of rod photoreceptors. In the RP mouse model, inhibitors of these enzymes blocked rod degeneration, preserved vision and affected the expression of multiple genes including maintenance of rod-specific transcripts and downregulation those involved in inflammation, gliosis and cell death. The neuroprotective activity of LSD1 inhibitors includes two pathways. First, through targeting histone modifications, they increase accessibility ...

The external pallidum (GPe) plays a central role for basal ganglia functions and dynamics and, consequently, has been included in most computational studies of the basal ganglia. These studies considered the GPe as a homogeneous neural population. However, experimental studies have shown that the GPe contains at least two distinct cell types (prototypical and arkypallidal cells). In this work, we provide in silico insight into how pallidal heterogeneity modulates dynamic regimes inside the GPe and how they affect the GPe response to oscillatory input. We derive a mean-field model of the GPe system from a microscopic spiking neural network of recurrently coupled prototypical and arkypallidal neurons. Using bifurcation analysis, we examine the influence of dopamine-dependent changes of intra-pallidal connectivity on the GPe dynamics. We find that increased self-inhibition of prototypical cells can induce oscillations, whereas increased inhibition of prototypical cells by arkypallidal cells leads to the emer...

The cortical subplate is critical in regulating the entry of thalamocortical sensory afferents into the cortex. These afferents reach the subplate at embryonic day (E)15.5 in the mouse, but “wait” for several days, entering the cortical plate postnatally. We report that when transcription factor Lhx2 is lost in E11.5 cortical progenitors, which give rise to subplate neurons, thalamocortical afferents display premature, exuberant ingrowth into the E15.5 cortex. Embryonic mutant subplate neurons are correctly positioned below the cortical plate, but they display an altered transcriptome and immature electrophysiological properties during the waiting period. The sensory thalamus in these cortex-specific Lhx2 mutants displays atrophy and by postnatal day (P) 7, sensory innervation to the cortex is nearly eliminated leading to a loss of the somatosensory barrels. Strikingly, these phenotypes do not manifest if Lhx2 is lost in postmitotic subplate neurons, and the transcriptomic dysregulation in the subplate res...