Cold Spring Harbor symposia on quantitative biology最新文献

Supported by technological advances and collaborative efforts, psychiatric genetics has provided robust genetic findings in the past decade, particularly through genome-wide association studies (GWASs). However, translating these genetic findings into biological mechanisms and new therapies has been enormously challenging because of the complexity of their interpretation. Furthermore, the heterogeneity among patients with the same diagnosis, such as schizophrenia or major depressive disorder, challenges the biological validity of existing categorical approaches in clinical nosology, which is further complicated by the pleiotropic nature of many genetic variants across multiple disorders. Therefore, in the post-GWAS era, the greatest challenge lies in integrating such enriched genetic information with functional dimensions of neurobiological measures and observable behaviors. In this integration, the causal inference from genotypes to phenotypes through intermediate biological processes is of particular importance. In this review, we aim to construct an intellectual framework in which we may obtain causal, mechanistic insights into how multifactorial etiologies-in particular, many genetic variants-affect downstream biological pathways that lead to dimensions of psychiatric relevance.

We wanted to understand the brain circuitry that awakens the individual when there is elevated CO₂ or low O₂ (e.g., during sleep apnea or asphyxia). The sensory signals for high CO₂ and low O₂ all converge on the parabrachial nucleus (PB) of the pons, which contains neurons that project to the forebrain. So, we first deleted the vesicular glutamate transporter 2, necessary to load glutamate into synaptic vesicles, from neurons in the PB, and showed that this prevents awakening to high CO₂ or low O₂ We then showed that PB neurons that express calcitonin gene-related peptide (CGRP) show cFos staining during high CO₂ Using CGRP-Cre-ER mice, we expressed the inhibitory opsin archaerhodopsin just in the PB^CGRP neurons. Photoinhibition of the PB^CGRP neurons effectively prevented awakening to high CO₂, as did photoinhibition of their terminals in the basal forebrain, amygdala, and lateral hypothalamus. The PB^CGRP neurons are a key mediator of the wakening response to apnea.

Psychiatry faces a number of challenges as a field. These include the high individual and societal costs of mental illnesses, overlapping and heterogeneous diagnoses, a complete lack of biomarkers, and treatments that, although efficacious for some, leave many without adequate relief. On the other hand, scientific and technical advances present considerable opportunities, especially in genomics, computational and theoretical approaches, and neural circuit technologies. The National Institute of Mental Health is committed to taking advantage of these opportunities to address the challenges of psychiatry, in the service of achieving our mission of transforming the understanding and treatment of mental illnesses.

Studies in patients and mouse models have pinpointed a precise zone in the cerebral cortex selectively vulnerable to the earliest stages of Alzheimer's disease (AD): the borderzone covering the entorhinal and perirhinal cortical areas. An independent series of studies has revealed that this entorhinal-perirhinal borderzone is a central cortical hub, with a distinct connectivity pattern across the cerebral hemispheres. Here we develop a hypothesis that explains how this distinct network feature interacts with established pathogenic drivers of AD in explaining the disease's regional vulnerability and suggests how it acts as an anatomical source of disease spread.

Three unbiased lines of research have commonly pointed to the benefits of enhanced levels of nicotinamide adenine dinucleotide (NAD⁺) to diseased or damaged neurons. Mice carrying a triplication of the gene encoding the culminating enzyme in NAD⁺ salvage from nicotinamide, NMNAT, are protected from a variety of insults to axons. Protection from Wallerian degeneration of axons is also observed in flies and mice bearing inactivating mutations in the SARM1 gene. Functional studies of the SARM1 gene product have revealed the presence of an enzymatic activity directed toward the hydrolysis of NAD⁺ Finally, an unbiased drug screen performed in living mice led to the discovery of a neuroprotective chemical designated P7C3. Biochemical studies of the P7C3 chemical show that it can enhance recovery of NAD⁺ from nicotinamide by activating NAMPT, the first enzyme in the salvage pathway. In combination, these three unrelated research endeavors offer evidence of the benefits of enhanced NAD⁺ levels to damaged neurons.

The maturation of the prefrontal cortex (PFC) during adolescence is thought to be important for cognitive and affective development and mental health risk. Whereas many summaries of adolescent development have focused on dendritic spine pruning and gray matter thinning in the PFC during adolescence, we highlight recent rodent data from our laboratory and others to call attention to continued synapse formation and plasticity in the adolescent period in specific cell types and circuits. In particular, we highlight changes in inhibitory neurotransmission onto intratelencephalic (IT-type) projecting cortical neurons and late expansion of connectivity between the amygdala and PFC and the ventral tegmental area and PFC. Continued work on these "late blooming" synapses in specific cell types and circuits, and their interrelationships, will illuminate new opportunities for understanding and shaping the biology of adolescent development. We also address which aspects of adolescent PFC development are dependent on pubertal processes.

We summarize a new approach to neuromodulator detection that provides colocalized detection of dopamine, serotonin, and norepinephrine at subsecond timescales and promises to provide submillisecond estimates of the same. The methodology, elastic net electrochemistry, is used to estimate dopamine and serotonin in the striatum of conscious human subjects during active decision-making. We show a proof-of-principle example of the same method working on commercially available depth electrodes in common use for epilepsy monitoring and neurosurgical planning in humans, which further promises to make such electrodes sources of fast neuromodulator information never before available in human subjects. We discuss the implications of this methodology for making direct tests in humans of the computations carried by these three important neuromodulatory systems. The methods also promise great utility in model organisms, but this chapter focuses on the possibilities for human use.