Advances in single-cell technologies have led to the discovery and characterization of new brain cell types, which in turn lead to a better understanding of the pathogenesis of Alzheimer's disease (AD). Here, we present a detailed analysis of single-nucleus (sn)RNA-seq data for three stages of AD from middle temporal gyrus and compare it with snRNA-seq data from the prefrontal cortices from individuals with alcohol use disorder (AUD). We observed a significant decrease in both inhibitory and excitatory neurons, in general agreement with previous reports. We observed several cell-type–specific gene expressions and pathway dysregulations that delineate AD stages. Endothelial and vascular leptomeningeal cells showed the greatest degree of gene expression changes. Cell-type–specific evidence of neurodegeneration was seen in multiple neuronal cell types particularly in somatostatin and Layer 5 extratelencephalic neurons, among others. Evidence of inflammatory responses was seen in non-neuronal cells, particular...

The formation and precise positioning of axons and dendrites are crucial for the development of neural circuits. Although juxtacrine signaling via cell–cell contact is known to influence these processes, the specific structures and mechanisms regulating neuronal process positioning within the central nervous system (CNS) remain to be fully identified. Our study investigates motoneuron 24 (MN24) in the Drosophila embryonic CNS, which is characterized by a complex yet stereotyped axon projection pattern, known as “axonal routing.” In this motoneuron, the primary dendritic branches project laterally toward the midline, specifically emerging at the sites where axons turn. We observed that Scp2-positive neurons contribute to the lateral fascicle structure in the ventral nerve cord (VNC) near MN24 dendrites. Notably, the knockout of the Down syndrome cell adhesion molecule ( Dscam1 ) results in the loss of dendrites and disruption of proper axonal routing in MN24, while not affecting the formation of the fascicl...

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults, and people with TLE exhibit higher rates of reproductive endocrine dysfunction. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons regulate reproductive function in mammals by regulating gonadotropin secretion from the anterior pituitary. Previous research demonstrated GnRH neuron hyperexcitability in both sexes in the intrahippocampal kainic acid (IHKA) mouse model of TLE. Fast-inactivating A-type ( I A) and delayed rectifier K-type ( I K) K+ currents play critical roles in modulating neuronal excitability, including in GnRH neurons. Here, we tested the hypothesis that GnRH neuron hyperexcitability is associated with reduced I A and I K conductances. At 2 months after IHKA or control saline injection, when IHKA mice exhibit chronic epilepsy, we recorded GnRH neuron excitability, I A, and I K using whole-cell patch-clamp electrophysiology. GnRH neurons from both IHKA male and diestrus female GnRH-GFP mice exhibited hyperexcit...

Animals have evolved innate responses to cues including social, food, and predator odors. In the natural environment, animals are faced with choices that involve balancing risk and reward where innate significance may be at odds with internal need. The ability to update the value of a cue through learning is essential for navigating changing and uncertain environments. However, the mechanisms involved in this modulation are not well defined in mammals. We have established a new olfactory assay that challenges a thirsty mouse to choose an aversive odor over an attractive odor in foraging for water, thus overriding their innate behavioral response to odor. Innately, mice prefer the attractive odor port over the aversive odor port. However, decreasing the probability of water at the attractive port leads mice to prefer the aversive port, reflecting a learned override of the innate response to the odors. The orbitofrontal cortex (OFC) is a fourth-order olfactory brain area, involved in flexible value associati...

It is a common belief that memories, over time, become progressively independent of the hippocampus and are gradually stored in cortical areas. This view is mainly based on evidence showing that prefrontal cortex (PFC) manipulations impair the retrieval of remote memories, while hippocampal inhibition does not. More controversial is whether activity in the medial PFC is required immediately after learning to initiate consolidation. Another question concerns functional differences among PFC subregions in forming and storing remote memories. To address these issues, we directly contrasted the effects of loss-of-function manipulations of the anterior cingulate cortex (aCC) and the ventromedial PFC, which includes the infralimbic (IL) and prelimbic (PL) cortices, before testing and immediately after training on the ability of CD1 mice to recall the hidden platform location in the Morris water maze. We injected an AAV carrying the hM4Di receptor into the PL–IL or aCC. Interestingly, pretest administrations of c...

In the presence of temporally organized stimuli, there is a tendency to entrain to the beat, even at the neurological level. Previous research has shown that when adults listen to rhythmic stimuli and are asked to imagine the beat, their neural responses are the same as when the beat is physically accented. The current study explores the neural processing of simple beat structures where the beat is physically accented or inferred from a previously presented physically accented beat structure in a passive listening context. We further explore the associations of these neural correlates with behavioral and self-reported measures of musicality. Fifty-seven participants completed a passive listening EEG paradigm, a behavioral rhythm discrimination task, and a self-reported musicality questionnaire. Our findings suggest that when the beat is physically accented, individuals demonstrate distinct neural responses to the beat in the beta (13–23 Hz) and gamma (24–50 Hz) frequency bands. We further find that the neu...

This article allows readers to assess their ability to detect errors in thinking in seven case histories of psychologists’ thoughts about cognitive science. It explains the nature of the errors and shows that some of them reflect faulty reasoning. It presents a “model method” to improve reasoning. It is based on the theory of mental models, which gives a general account of how individuals think, both deductively and indicatively, and which postulates that individuals construct mental models of possibilities in the world. The model method enhances both the accuracy and speed of reasoning. The article concludes with some general reflections on the role of knowledge of meanings, the world, and context in thinking.

Two-photon calcium imaging allows for the activity readout of large populations of neurons at single cell resolution in living organisms, yielding new insights into how the brain processes information. Holographic optogenetics allows us to trigger activity of this population directly, raising the possibility of injecting information into a living brain. Optogenetic triggering of activity that mimics “natural” information, however, requires identification of stimulation targets based on real-time analysis of the functional network. We have developed NeuroART (Neuronal Analysis in Real Time), software that provides real-time readout of neuronal activity integrated with downstream analysis of correlations and synchrony and of sensory metadata. On the example of auditory stimuli, we demonstrate real-time inference of the contribution of each neuron in the field of view to sensory information processing. To avoid the limitations of microscope hardware and enable collaboration of multiple research groups, NeuroA...

Despite decades of preclinical investigation, there remains limited understanding of the etiology and biological underpinnings of anxiety disorders. Sensitivity to potential threat is characteristic of anxiety-like behavior in humans and rodents, but traditional rodent behavioral tasks aimed to assess threat responsiveness lack translational value, especially with regard to emotionally valenced stimuli. Therefore, development of novel preclinical approaches to serve as analogues to patient assessments is needed. In humans, the fearful face task is widely used to test responsiveness to socially communicated threat signals. In rats, ultrasonic vocalizations (USVs) are analogous social cues associated with positive or negative affective states that can elicit behavioral changes in the receiver. It is therefore likely that when rats hear aversive alarm call USVs (22 kHz), they evoke translatable changes in brain activity comparable with the fearful face task. We used functional magnetic resonance imaging in ma...

This study aims to explore the correlation of serum thyroid hormone levels to cognitive impairments in Parkinson's disease (PD) patients. In this retrospective study, 106 Chinese patients without cognitive impairments and 94 patients with cognitive impairments, including 55 with mild cognitive impairment (PD-MCI) and 39 with PD dementia (PDD), were analyzed. Clinical data regarding the PD assessments, including disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) Part 3 scores, and Hoehn and Yahr (H–Y) staging, were analyzed. Cognitive functions were evaluated using the Montreal Cognitive Assessment score. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3), were measured using ELISA. Significantly altered H–Y staging, disease duration, and UPDRS Part 3 scores were observed in PD patients with cognitive impairment compared with those without. Serum levels of FT3 were significantly decreased, while FT4 and TSH levels were significantly eleva...