RESUMEN
Alcohol use disorder is a major public health concern in the United States. Recent work has suggested a link between chronic alcohol consumption and the development of tauopathy disorders, such as Alzheimer's disease and frontotemporal dementia. However, relatively little work has investigated changes in neural circuitry involved in both tauopathy disorders and alcohol use disorder. The locus coeruleus (LC) is the major noradrenergic nucleus in the brain and is one of the earliest sites to be affected by tau lesions. The LC is also implicated in the rewarding effects of ethanol and alcohol withdrawal. In this study we assessed effects of long-term ethanol consumption and tauopathy on the physiology of LC neurons. Male and female P301S mice, a humanized transgenic mouse model of tauopathy, underwent 16 weeks of intermittent access to 20% ethanol from 3 to 7 months of age. We observed higher total alcohol consumption in female mice regardless of genotype. Male P301S mice consumed more ethanol and had a greater preference for ethanol than wild-type (WT) males. At the end of the drinking study, LC function was assessed using ex vivo whole cell electrophysiology. We found significant changes in excitatory inputs to the LC due to both ethanol and genotype. We found significantly increased excitability of the LC due to ethanol with greater effects in female P301S mice than in female WT mice. Our study identifies significant changes in the LC due to interactions between tauopathy and long-term ethanol use. These findings could have important implications regarding LC activity and changes in behavior due to both ethanol- and tauopathy-related dementia.
Asunto(s)
Alcoholismo , Síndrome de Abstinencia a Sustancias , Tauopatías , Ratones , Masculino , Femenino , Animales , Locus Coeruleus/patología , Alcoholismo/patología , Tauopatías/genética , Tauopatías/patología , Ratones Transgénicos , Etanol , Consumo de Bebidas Alcohólicas/genéticaRESUMEN
Psychiatric disorders are highly heritable pathologies of altered neural circuit functioning. How genetic mutations lead to specific neural circuit abnormalities underlying behavioral disruptions, however, remains unclear. Using circuit-selective transgenic tools and a mouse model of maladaptive social behavior (ArpC3 mutant), we identify a neural circuit mechanism driving dysfunctional social behavior. We demonstrate that circuit-selective knockout (ctKO) of the ArpC3 gene within prefrontal cortical neurons that project to the basolateral amygdala elevates the excitability of the circuit neurons, leading to disruption of socially evoked neural activity and resulting in abnormal social behavior. Optogenetic activation of this circuit in wild-type mice recapitulates the social dysfunction observed in ArpC3 mutant mice. Finally, the maladaptive sociability of ctKO mice is rescued by optogenetically silencing neurons within this circuit. These results highlight a mechanism of how a gene-to-neural circuit interaction drives altered social behavior, a common phenotype of several psychiatric disorders.
Asunto(s)
Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Trastornos Mentales/fisiopatología , Corteza Prefrontal/fisiopatología , Complejo 2-3 Proteico Relacionado con la Actina/genética , Animales , Complejo Nuclear Basolateral/metabolismo , Citoesqueleto , Modelos Animales de Enfermedad , Masculino , Ratones , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatología , Neuronas , Optogenética , Técnicas de Placa-Clamp , Corteza Prefrontal/metabolismo , Conducta SocialRESUMEN
Although instruction on meiosis is repeated many times during the undergraduate curriculum, many students show poor comprehension even as upper-level biology majors. We propose that the difficulty lies in the complexity of understanding DNA, which we explain through a new model, the DNA triangle The DNA triangle integrates three distinct scales at which one can think about DNA: chromosomal, molecular, and informational Through analysis of interview and survey data from biology faculty and students through the lens of the DNA triangle, we illustrate important differences in how novices and experts are able to explain the concepts of ploidy, homology, and mechanism of homologous pairing Similarly, analysis of passages from 16 different biology textbooks shows a large divide between introductory and advanced material, with introductory books omitting explanations of meiosis-linked concepts at the molecular level of DNA. Finally, backed by textbook findings and feedback from biology experts, we show that the DNA triangle can be applied to teaching and learning meiosis. By applying the DNA triangle to topics on meiosis we present a new framework for educators and researchers that ties concepts of ploidy, homology, and mechanism of homologous pairing to knowledge about DNA on the chromosomal, molecular, and informational levels.
Asunto(s)
Biología/educación , Curriculum , Aprendizaje , Meiosis , Estudiantes , ADN , HumanosRESUMEN
Inhibitory synapses dampen neuronal activity through postsynaptic hyperpolarization. The composition of the inhibitory postsynapse and the mechanistic basis of its regulation, however, remain poorly understood. We used an in vivo chemico-genetic proximity-labeling approach to discover inhibitory postsynaptic proteins. Quantitative mass spectrometry not only recapitulated known inhibitory postsynaptic proteins but also revealed a large network of new proteins, many of which are either implicated in neurodevelopmental disorders or are of unknown function. Clustered regularly interspaced short palindromic repeats (CRISPR) depletion of one of these previously uncharacterized proteins, InSyn1, led to decreased postsynaptic inhibitory sites, reduced the frequency of miniature inhibitory currents, and increased excitability in the hippocampus. Our findings uncover a rich and functionally diverse assemblage of previously unknown proteins that regulate postsynaptic inhibition and might contribute to developmental brain disorders.
Asunto(s)
Encefalopatías/metabolismo , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Inhibición Neural , Densidad Postsináptica/metabolismo , Proteoma/metabolismo , Animales , Encefalopatías/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Espectrometría de Masas , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutación , Proteínas del Tejido Nervioso/genéticaRESUMEN
Cellular processes that rely on knowledge of molecular behavior are difficult for students to comprehend. For example, thorough understanding of meiosis requires students to integrate several complex concepts related to chromosome structure and function. Using a grounded theory approach, we have unified classroom observations, assessment data, and in-depth interviews under the theory of knowledge transfer to explain student difficulties with concepts related to chromosomal behavior. In this paper, we show that students typically understand basic chromosome structure but do not activate cognitive resources that would allow them to explain macromolecular phenomena (e.g., homologous pairing during meiosis). To improve understanding of topics related to genetic information flow, we suggest that instructors use pedagogies and activities that prime students for making connections between chromosome structure and cellular processes.