Alexandra O. Cohen

Bio: Alexandra O. Cohen is an academic researcher from New York University. The author has contributed to research in topics: Medicine & Cognition. The author has an hindex of 14, co-authored 28 publications receiving 1388 citations. Previous affiliations of Alexandra O. Cohen include Cornell University.

Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells

Abstract: It has long been hypothesized that abnormalities in lipid biology contribute to degenerative brain diseases. Consistent with this, emerging epidemiologic evidence links lipid alterations with Parkinson disease (PD), and disruption of lipid metabolism has been found to predispose to α-synuclein toxicity. We therefore investigated whether Parkin, an E3 ubiquitin ligase found to be defective in patients with early onset PD, regulates systemic lipid metabolism. We perturbed lipid levels by exposing Parkin+/+ and Parkin-/- mice to a high-fat and -cholesterol diet (HFD). Parkin-/- mice resisted weight gain, steatohepatitis, and insulin resistance. In wild-type mice, the HFD markedly increased hepatic Parkin levels in parallel with lipid transport proteins, including CD36, Sr-B1, and FABP. These lipid transport proteins were not induced in Parkin-/- mice. The role of Parkin in fat uptake was confirmed by increased oleate accumulation in hepatocytes overexpressing Parkin and decreased uptake in Parkin-/- mouse embryonic fibroblasts and patient cells harboring complex heterozygous mutations in the Parkin-encoding gene PARK2. Parkin conferred this effect, in part, via ubiquitin-mediated stabilization of the lipid transporter CD36. Reconstitution of Parkin restored hepatic fat uptake and CD36 levels in Parkin-/- mice, and Parkin augmented fat accumulation during adipocyte differentiation. These results demonstrate that Parkin is regulated in a lipid-dependent manner and modulates systemic fat uptake via ubiquitin ligase-dependent effects. Whether this metabolic regulation contributes to premature Parkinsonism warrants investigation.

When Is an Adolescent an Adult? Assessing Cognitive Control in Emotional and Nonemotional Contexts

Abstract: An individual is typically considered an adult at age 18, although the age of adulthood varies for different legal and social policies. A key question is how cognitive capacities relevant to these policies change with development. The current study used an emotional go/no-go paradigm and functional neuroimaging to assess cognitive control under sustained states of negative and positive arousal in a community sample of one hundred ten 13- to 25-year-olds from New York City and Los Angeles. The results showed diminished cognitive performance under brief and prolonged negative emotional arousal in 18- to 21-year-olds relative to adults over 21. This reduction in performance was paralleled by decreased activity in fronto-parietal circuitry, implicated in cognitive control, and increased sustained activity in the ventromedial prefrontal cortex, involved in emotional processes. The findings suggest a developmental shift in cognitive capacity in emotional situations that coincides with dynamic changes in prefrontal circuitry. These findings may inform age-related social policies.

Teens impulsively react rather than retreat from threat

Abstract: There is a significant inflection in risk taking and criminal behavior during adolescence, but the basis for this increase remains largely unknown. An increased sensitivity to rewards has been suggested to explain these behaviors, yet juvenile offences often occur in emotionally charged situations of negative valence. How behavior is altered by changes in negative emotional processes during adolescence has received less attention than changes in positive emotional processes. The current study uses a measure of impulsivity in combination with cues that signal threat or safety to assess developmental changes in emotional responses to threat cues. We show that adolescents, especially males, impulsively react to threat cues relative to neutral ones more than adults or children, even when instructed not to respond. This adolescent-specific behavioral pattern is paralleled by enhanced activity in limbic cortical regions implicated in the detection and assignment of emotional value to inputs and in the subsequent regulation of responses to them when successfully suppressing impulsive responses to

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Annual Research Review: On the relations among self-regulation, self-control, executive functioning, effortful control, cognitive control, impulsivity, risk-taking, and inhibition for developmental psychopathology

Abstract: Background Self-regulation (SR) is central to developmental psychopathology, but progress has been impeded by varying terminology and meanings across fields and literatures. Methods The present review attempts to move that discussion forward by noting key sources of prior confusion such as measurement-concept confounding, and then arguing the following major points. Results First, the field needs a domain-general construct of SR that encompasses SR of action, emotion, and cognition and involves both top-down and bottom-up regulatory processes. This does not assume a shared core process across emotion, action, and cognition, but is intended to provide clarity on the extent of various claims about kinds of SR. Second, top-down aspects of SR need to be integrated. These include (a) basic processes that develop early and address immediate conflict signals, such as cognitive control and effortful control (EC), and (b) complex cognition and strategies for addressing future conflict, represented by the regulatory application of complex aspects of executive functioning. Executive function (EF) and cognitive control are not identical to SR because they can be used for other activities, but account for top-down aspects of SR at the cognitive level. Third, impulsivity, risk-taking, and disinhibition are distinct although overlapping; a taxonomy of the kinds of breakdowns of SR associated with psychopathology requires their differentiation. Fourth, different aspects of the SR universe can be organized hierarchically in relation to granularity, development, and time. Low-level components assemble into high-level components. This hierarchical perspective is consistent across literatures. Conclusions It is hoped that the framework outlined here will facilitate integration and cross-talk among investigators working from different perspectives, and facilitate individual differences research on how SR relates to developmental psychopathology.