Race and the Ivory Tower: An Antiracism Exercise for an Undergraduate Neuroscience Classroom.

This article details an antiracism exercise completed in an introductory undergraduate neuroscience class. Students completed an online pre-class multimedia module entitled "Race and the Ivory Tower" covering racism in science and medicine, the neuroscience behind bias, and the impact of race and racism on health outcomes. The module included two videos, one podcast, and a peer-reviewed journal article, alongside several optional additional resources written for both academic and lay audiences. After completing the module, students participated in an open-ended online discussion followed by an anonymous survey to elicit feedback on the exercise. As a continuation of the antiracism exercise, students researched and reported on the work of a Black or nonwhite Hispanic/Latino scientist for a final project later in the semester. Sixty-eight of 69 students participated in the discussion, and the majority discussed the neuroscience of bias and public health effects of racism. Most students also discussed the importance of the module contents or further questions that they would explore. Sixty of 69 students answered the anonymous survey, where most students reported a better understanding of racism after interacting with the content. Additionally, most students felt better prepared to discuss racism in science and medicine and more able to identify unconscious bias. Finally, students reported that they enjoyed the module contents and online discussion. Overall, this exercise effectively introduced students to the ongoing challenge of racism in science and medicine through both scientific and sociological lenses. Students recognized the collective importance of the content, which was our goal as they represent the future leaders in neuroscience and medicine and should be equipped to address leading issues within their field.

Experience-dependent epigenomic reorganization in the hippocampus.

Using a hippocampus-dependent contextual threat learning and memory task, we report widespread, coordinated DNA methylation changes in CA1 hippocampus of Sprague-Dawley rats specific to threat learning at genes involved in synaptic transmission. Experience-dependent alternations in gene expression and DNA methylation were observed as early as 1 h following memory acquisition and became more pronounced after 24 h. Gene ontology analysis revealed significant enrichment of functional categories related to synaptic transmission in genes that were hypomethylated at 24 h following threat learning. Integration of these data sets with previously characterized epigenetic and transcriptional changes in brain disease states suggested significant overlap between genes regulated by memory formation and genes altered in memory-related neurological and neuropsychiatric diseases. These findings provide a comprehensive resource to aid in the identification of memory-relevant therapeutic targets. Our results shed new light on the gene expression and DNA methylation changes involved in memory formation, confirming that these processes are dynamic and experience-dependent. Finally, this work provides a roadmap for future studies to identify linkage of memory-associated genes to altered disease states.

Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1.

Aberrant gene expression within the hippocampus has recently been implicated in the pathogenesis of obesity-induced memory impairment. Whether a dysregulation of epigenetic modifications mediates this disruption in gene transcription has yet to be established. Here we report evidence of obesity-induced alterations in DNA methylation of memory-associated genes, including Sirtuin 1 (Sirt1), within the hippocampus, and thus offer a novel mechanism by which SIRT1 expression within the hippocampus is suppressed during obesity. Forebrain neuron-specific Sirt1 knock-out closely recapitulated the memory deficits exhibited by obese mice, consistent with the hypothesis that the high-fat diet-mediated reduction of hippocampal SIRT1 could be responsible for obesity-linked memory impairment. Obese mice fed a diet supplemented with the SIRT1-activating molecule resveratrol exhibited increased hippocampal SIRT1 activity and preserved hippocampus-dependent memory, further strengthening this conclusion. Thus, our findings suggest that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic dysregulation of SIRT1 within the hippocampus. SIGNIFICANCE STATEMENT: Previous studies have implicated transcriptional dysregulation within the hippocampus as being a relevant pathological concomitant of obesity-induced memory impairment, yet a deeper understanding of the basis for, and etiological significance of, transcriptional dysregulation in this context is lacking. Here we present the first evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, including Sirt1, within the hippocampus of obese mice. Furthermore, experiments using transgenic and pharmacological approaches strongly implicate reduced hippocampal SIRT1 as being a principal pathogenic mediator of obesity-induced memory impairment. This paper offers a novel working model that may serve as a conceptual basis for the development of therapeutic interventions for obesity-induced memory impairment.

Synaptic evidence for the efficacy of spaced learning.

The superiority of spaced vs. massed training is a fundamental feature of learning. Here, we describe unanticipated timing rules for the production of long-term potentiation (LTP) in adult rat hippocampal slices that can account for one temporal segment of the spaced trials phenomenon. Successive bouts of naturalistic theta burst stimulation of field CA1 afferents markedly enhanced previously saturated LTP if spaced apart by 1 h or longer, but were without effect when shorter intervals were used. Analyses of F-actin-enriched spines to identify potentiated synapses indicated that the added LTP obtained with delayed theta trains involved recruitment of synapses that were "missed" by the first stimulation bout. Single spine glutamate-uncaging experiments confirmed that less than half of the spines in adult hippocampus are primed to undergo plasticity under baseline conditions, suggesting that intrinsic variability among individual synapses imposes a repetitive presentation requirement for maximizing the percentage of potentiated connections. We propose that a combination of local diffusion from initially modified spines coupled with much later membrane insertion events dictate that the repetitions be widely spaced. Thus, the synaptic mechanisms described here provide a neurobiological explanation for one component of a poorly understood, ubiquitous aspect of learning.

Myosin II motor activity in the lateral amygdala is required for fear memory consolidation.

Learning induces dynamic changes to the actin cytoskeleton that are required to support memory formation. However, the molecular mechanisms that mediate filamentous actin (F-actin) dynamics during learning and memory are poorly understood. Myosin II motors are highly expressed in actin-rich growth structures including dendritic spines, and we have recently shown that these molecular machines mobilize F-actin in response to synaptic stimulation and learning in the hippocampus. In this study, we report that Myosin II motors in the rat lateral amygdala (LA) are essential for fear memory formation. Pretraining infusions of the Myosin II inhibitor, blebbistatin (blebb), disrupted long term memory, while short term memory was unaffected. Interestingly, both post-training and pretesting infusions had no effect on memory formation, indicating that Myosin II motors operate during or shortly after learning to promote memory consolidation. These data support the idea that Myosin II motor-force generation is a general mechanism that supports memory consolidation in the mammalian CNS.

Transcriptional and epigenetic regulation of Hebbian and non-Hebbian plasticity.

The epigenome is uniquely positioned as a point of convergence, integrating multiple intracellular signaling cascades into a cohesive gene expression profile necessary for long-term behavioral change. The last decade of neuroepigenetic research has primarily focused on learning-induced changes in DNA methylation and chromatin modifications. Numerous studies have independently demonstrated the importance of epigenetic modifications in memory formation and retention as well as Hebbian plasticity. However, how these mechanisms operate in the context of other forms of plasticity is largely unknown. In this review, we examine evidence for epigenetic regulation of Hebbian plasticity. We then discuss how non-Hebbian forms of plasticity, such as intrinsic plasticity and synaptic scaling, may also be involved in producing the cellular adaptations necessary for learning-related behavioral change. Furthermore, we consider the likely roles for transcriptional and epigenetic mechanisms in the regulation of these plasticities. In doing so, we aim to expand upon the idea that epigenetic mechanisms are critical regulators of both Hebbian and non-Hebbian forms of plasticity that ultimately drive learning and memory.

Myosin IIb regulates actin dynamics during synaptic plasticity and memory formation.

Reorganization of the actin cytoskeleton is essential for synaptic plasticity and memory formation. Presently, the mechanisms that trigger actin dynamics during these brain processes are poorly understood. In this study, we show that myosin II motor activity is downstream of LTP induction and is necessary for the emergence of specialized actin structures that stabilize an early phase of LTP. We also demonstrate that myosin II activity contributes importantly to an actin-dependent process that underlies memory consolidation. Pharmacological treatments that promote actin polymerization reversed the effects of a myosin II inhibitor on LTP and memory. We conclude that myosin II motors regulate plasticity by imparting mechanical forces onto the spine actin cytoskeleton in response to synaptic stimulation. These cytoskeletal forces trigger the emergence of actin structures that stabilize synaptic plasticity. Our studies provide a mechanical framework for understanding cytoskeletal dynamics associated with synaptic plasticity and memory formation.

Cortical DNA methylation maintains remote memory.

A behavioral memory's lifetime represents multiple molecular lifetimes, suggesting the necessity for a self-perpetuating signal. One candidate is DNA methylation, a transcriptional repression mechanism that maintains cellular memory throughout development. We found that persistent, gene-specific cortical hypermethylation was induced in rats by a single, hippocampus-dependent associative learning experience and pharmacologic inhibition of methylation 1 month after learning disrupted remote memory. We propose that the adult brain utilizes DNA methylation to preserve long-lasting memories.