Virginia Tech neuroscientists have uncovered a mitochondrial process that supports the brain cells critical for learning, memory, and social recognition.
Category: neuroscience – Page 7
A new Yale study provides a fuller picture of the genetic changes that shaped the evolution of the human brain, and how the process differed from the evolution of chimpanzees.
For the study, published Jan. 30 in the journal Cell, researchers focused on a class of genetic switches known as Human Accelerated Regions (HARs), which regulate when, where, and at what level genes are expressed during evolution.
While past research theorized that HARs may act by controlling different genes in humans compared to chimpanzees, our closest primate relative, the new findings show that HARs fine-tune the expression of genes that are already shared between humans and chimpanzees, influencing how neurons are born, develop, and communicate with each other.
Uniquely human features of neocortical development and maturation are not only intriguing for their implications in human-specific cognitive abilities, but they are also vulnerable to dysregulation which could cause or contribute to distinctly human brain disorder pathophysiology. The human cerebral cortex is essential for both cognition and emotional processing and dysregulation of these processes of the cortex are associated with a wide range of brain disorders including schizophrenia (SZ), autism spectrum disorder (ASD), Parkinson’s disease (PD), and Alzheimer’s disease (AD) (Berman and Weinberger, 1991; Rubenstein, 2011; Xu et al., 2019). Much remains to be learned about the mechanisms governing cortical expansion and responses to pathogenesis between human and non-human primates (NHPs) (Otani et al., 2016). Understanding these differences could shed light on the underlying mechanisms responsible for human-specific brain disorders and lead to the identification of key targets for the development of effective therapies.
Subtle differences observed by comparing human neurodevelopment to that of our closest evolutionary relatives could reveal underlying mechanisms, including genomic or transcriptional differences, contributing to varied phenotypes (Pollen et al., 2019). Human-specific responses to pathogenesis might be elucidated in a similar manner; by comparing brain pathophysiology of humans to our non-human primate counterparts (Hof et al., 2004). Although rodent models have taught us much about basic mammalian brain development and disorders (Fernando and Robbins, 2011), comparing governing processes and responses to species more closely related to humans can reduce the number of variables allowing for the identification of specific mechanisms responsible for observed deviations. Studies analyzing induced pluripotent stem cells (iPSCs) derived from humans, chimpanzees, and bonobos (Pan paniscus) show large sets of differentially expressed genes between human and NHP iPSCs. Perhaps the most compelling differentially expressed genes are those related to increased long interspersed element-1 (LINE-1) mobility in chimpanzees and bonobos, which could have implications on the rates of genetic divergence among species, and alternative mechanisms of pluripotency maintenance in chimpanzees (Marchetto et al., 2013; Gallego Romero et al., 2015). Furthermore, when human and NHP iPSCs were differentiated to neurons, they displayed distinctive migratory patterns at the neural progenitor cell (NPC) stage followed by contrasting morphology and timing of maturation in neurons (Marchetto et al., 2019). Despite the ability of two-dimensional (2D) PSC-derived neural cultures to demonstrate basic organization and transcriptomic changes of early brain development (Yan et al., 2013), while retaining the genetic background of the somatic cells from which they are reprogrammed, they lack the ability to develop complex cytoarchitecture, recapitulate advanced spatiotemporal transcriptomics, and brain region interconnectivity (including migration and axon guidance) of ensuing primate brain development (Soldner and Jaenisch, 2019). Intricate cellular heterogeneity, complex architecture, and interconnectivity of neurodevelopment, in addition to pathogenic responses, could be observed by comparing human and NHP brain tissues; however, ethical concerns and the inaccessibility of pre-and postnatal primate brain tissues limits the feasibility of such studies.
While brain organoids might be a long way from forming or sharing thoughts with us, they could still teach us much about ourselves. Brain organoids are three-dimensional (3D), PSC-derived structures that display complex radial organization of expanding neuroepithelium following embedding in an extracellular matrix like Matrigel and can recapitulate some subsequent processes of neurodevelopment including neurogenesis, gliogenesis, synaptogenesis, heterogenous cytoarchitecture, cell and axon migration, myelination of axons, and spontaneously-active neuronal networks (Lancaster et al., 2013; Bagley et al., 2017; Birey et al., 2017; Quadrato et al., 2017; Xiang et al., 2017; Marton et al., 2019; Shaker et al., 2021). It is likely that all these features of neurodevelopment are governed by some degree of specifies-specific dynamics. Brain organoids can be generated from human and NHP PSCs and, since some pathways regulating neural induction and brain region specification are well conserved in primates, both unguided cerebral organoids and guided brain region specific organoids can be generated (Mora-Bermúdez et al., 2016; Field et al., 2019; Kanton et al., 2019). Additional protocols have been established for the derivation of brain region specific organoids from human PSCs (hPSCs), including dorsal forebrain, ventral forebrain, midbrain, thalamus, basal ganglia, cerebellum, and telencephalic organoids (Muguruma et al., 2015; Sakaguchi et al., 2015; Jo et al., 2016; Bagley et al., 2017; Birey et al., 2017; Watanabe et al., 2017; Xiang et al., 2017, 2019; Qian et al., 2018). With some modifications, these methods could prove to be successful in establishing brain region-specific organoids from a variety of NHP PSC lines allowing for the reproducible comparison of homogeneous, human-specific neurodevelopment and brain disorder pathophysiology in brain regions beyond the cortex.
A stem cell-based technology provides a unique window on illnesses such as autism and schizophrenia.
The brain of humans and other animals is known to contribute to the protection of the body from infections. Past studies have unveiled the existence of the so-called conditioned immune response (CIR), which is a form of Pavlovian conditioning that entails the formation of mental associations between specific sensory stimuli (e.g., a specific odor, taste, etc.) and immunomodulatory agents (i.e., a substance that influences the immune system).
For instance, if an animal tastes a particular food shortly before becoming ill several times, re-experiencing the same taste can evoke an aversive response and even trigger an anticipatory immune response. While this CIR is now well-documented, its neural underpinnings so far remain poorly understood.
Researchers at University of Haifa recently carried out a study aimed at better understanding the neural pathways involved in these widely reported conditioned immune responses (CIRs). Their paper, published in Nature Neuroscience, outlines a neural pathway that appears to mediate the retrieval of CIRs in male mice.
Added Hofer, “Our results challenge traditional views about learning and memory. While the cerebral cortex has long been considered the brain’s primary centre for learning, memory and behavioral flexibility, we found the subcortical vLGN and not the visual cortex actually stores these crucial memories. This neural pathway can provide a link between cognitive neocortical processes and ‘hard-wired’ brainstem-mediated behaviors, enabling animals to adapt instinctive behaviors.”
The implications of the discoveries extend beyond the laboratory, the team suggests. Dysfunction of pathways through vLGN or impairments in eCB-dependent plasticity could contribute to fear and anxiety disorders and PTSD, the team suggested. “… targeting these pathways, for example, by using deep brain stimulation, or enhancing eCB-dependent plasticity within these circuits may facilitate suppression of maladaptive fear responses, suggesting new therapeutic strategies for fear-related disorders.”
Hofer stated, “Our findings could also help advance our understanding of what is going wrong in the brain when fear response regulation is impaired in conditions such as phobias, anxiety and PTSD. While instinctive fear reactions to predators may be less relevant for modern humans, the brain pathway we discovered exists in humans too. This could open new avenues for treating fear disorders by targeting vLGN circuits or localized endocannabinoid systems.”
DEA is used in industrial, agricultural, and consumer products.
“We knew that micropollutants can be incorporated into fatty molecules in the body, but we didn’t know how this occurs or what happens next,” Clardy said. “DEA’s metabolism into an immune signal was completely unexpected.”
The team proposes that DEA could be added to the growing list of biomarkers used to detect some cases of major depressive disorder.
Summary: New research reveals that brain cells use a muscle-like signaling mechanism to relay information over long distances. Scientists discovered that dendrites, the branch-like extensions of neurons, contain a structured network of contact sites that amplify calcium signals—similar to how muscles contract. These contact sites regulate calcium release, activating key proteins involved in learning and memory.
This mechanism explains how neurons process information received at specific points and relay it to the cell body. Understanding this process sheds light on synaptic plasticity, which underlies learning and memory formation. The findings could provide new insights into neurodegenerative diseases like Alzheimer’s.