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Colleen McClung

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Colleen Ann McClung is an American chronobiologist and neuroscientist. She is a tenured professor at the University of Pittsburgh, the director of the NIDA-funded Center for Adolescent Reward, Rhythms and Sleep (CARRS), and a fellow of the American College of Neuropsychopharmacology.

Education and career

In 1990, McClung began her undergraduate studies at the University of North Carolina at Chapel Hill, graduating in 1994 with Bachelor of Science in Biology and minor in Chemistry.[1] In 1995, McClung became a student at the graduate department of the University of Virginia, and in 2001 she received a PhD in biology from the same institution under the mentorship of Jay Hirsh.[2][3][4] In 2001, McClung started her postdoctoral work in the University of Texas Southwestern Medical Center Department of Psychiatry working with Eric J. Nestler until 2005.[2][4] From 2005 until 2011, she served as an assistant professor in the same department.[2] In 2011, McClung became an associate professor in the Department of Psychiatry at the University of Pittsburgh School of Medicine.[2][5] In 2017, she was promoted to professor.[2][6] In 2020, McClung became the director of the Center for Adolescent Reward, Rhythms and Sleep (CARRS).[7]

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Research

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Overview

McClung's research focuses on discovering, analyzing, and studying the molecular and biological mechanisms underlying psychiatric diseases such as drug addiction, schizophrenia, major depression, and bipolar disorder, with a primary interest in their association with circadian rhythms. During her Ph.D. McClung worked on using the fruit fly Drosophila melanogaster as a model system to study the genetics of drug sensitization.[8][9][10] She later investigated the relationship between circadian rhythms and the development of psychiatric disorders.[11] McClung has employed microarray technologies to examine gene expression changes in the mouse brain in the context of psychiatric disorders, particularly addiction.[12] Notably, her work has demonstrated that mice with a mutated CLOCK gene exhibit behaviors similar to human mania, including hyperactivity, reduced anxiety, and increased reward-seeking for substances such as cocaine and sucrose.[13] She also found that these mania-like behaviors can be reversed with chronic lithium treatment, mirroring therapeutic responses in humans with bipolar disorder.[14] In addition to lithium, McClung demonstrated that Clock mutant mice also respond to valproate, further supporting face validity of the mouse model in bipolar disorder.[15] McClung's research also aims to identify molecular components within the circadian system that may serve as potential targets for the development of novel psychiatric drugs.[16] Furthermore, McClung's work demonstrates how circadian rhythms influence vulnerability and resilience to stress, offering vital insight into mood disorders.[17]

CLOCK Involvement in Dopaminergic Neurotransmission

A 2005 study by McClung et al. was among the first to demonstrate that circadian genes, specifically the CLOCK gene, directly influence brain reward pathways and drug sensitivity. The study examined how the CLOCK gene affects dopaminergic reward circuitry, with a particular focus on sensitivity to cocaine. Using CLOCK mutant mice, the researchers found that these mice exhibited increased sensitivity to the rewarding effects of cocaine, elevated dopaminergic activity in the ventral tegmental area (VTA), and increased expression of genes associated with dopamine synthesis and signaling. These findings suggest that the CLOCK gene plays a role in regulating dopamine output.[18]

Application to Addiction and Mania

In 2007, McClung explored growing evidence that disruptions in circadian rhythms play a key role in the development and symptoms of bipolar disorder. This study focused on clock genes, including CLOCK, BMAL1, and PER, which regulate daily cycles of behavior and physiology. Animal studies in mice with mutated CLOCK genes showed behaviors resembling mania, including increased activity, reduced sleep, and heightened reward sensitivities. McClung hypothesized that altered function in these genes might underlie mood swings in bipolar patients based on these findings. From this study, it was concluded that targeting circadian rhythms has therapeutic potential for stabilizing mood and improving treatment outcomes for people with bipolar disorder. These therapies include light therapy, sleep regulation, and drugs that influence clock gene expression.[19]

In another study, McClung et al. observed that using RNAi to knock down CLOCK expression resulted in a unique behavioral phenotype: a mix of mania-like and depression-like behaviors. This phenotype directly reflects the mixed states observed in some bipolar disorder patients. Researchers specifically targeted the CLOCK gene in the ventral tegmental area (VTA), a brain region known to be important in mood and reward. It was observed that CLOCK knockdown in this area altered dopaminergic neuron firing rates, increasing dopaminergic activity, which likely contributed to the behavioral changes. The results of this study support the hypothesis that the circadian system is not just a global clock but also fine-tunes local brain function.[20]

Current Work

Circadian genes, brain circuitry, and neural cell metabolism

Dr. McClung’s recent work has discovered a bidirectional relationship between the molecular rhythms in nuclear and mitochondrial gene expression and antioxidant function in the rest of the cell.[21] These rhythms in cellular metabolism and circadian proteins (such as CLOCK) cooperate to regulate dopamine synthesis and the reward value for drugs including cocaine. Additional work found that astrocytes in the nucleus accumbens, a hub for reward regulation, have over 40% of their transcriptome exhibiting a diurnal rhythm.[22] Among these rhythmic genes were key metabolic pathways, such as lactate production, leading to altered reward behavior when the clock was disrupted. More broadly, disruptions of the suprachiasmatic nucleus were shown to correlate with increased measures of anxiety-like behavior in mice.[23] This shows the effects of rhythmic activity disruption (through increased or disrupted communication between central pacemaker cells) impact psychiatric disease-related behavior. She has made further contributions describing circadian disruptions across a variety of age-related disorders.[24]

Neural rhythms in the context of psychiatric and reward disorders

Dr. McClung has a wide range of work probing the molecular rhythm changes occurring in patients with psychiatric diseases, which are known to have circadian rhythm and sleep disruptions as defining features. Via genome-wide molecular rhythm detection techniques, McClung found that schizophrenia subjects undergo “circadian reprogramming” which is associated with the gain of rhythmicity in transcripts associated with mitochondrial function in the prefrontal cortex.[25] These rhythms drive differential expression patterns of schizophrenia-implicated genes, such as BDNF and GABA-related transcripts. Other work using sequencing technologies (such as RNA-seq) identified altered gene expression rhythms in striatal regions in subjects with psychosis, which is highly prevalent in bipolar disorder and a defining feature of schizophrenia.[26] Those with psychosis exhibited a substantial loss of rhythmicity in core clock genes, along with a gain of rhythmicity in glutamatergic signaling in the nucleus accumbens. Overall, McClung’s work is revealing the molecular mechanisms that may contribute to the dysfunction of certain brain regions in psychiatric disorders.

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Awards and honors

McClung has received numerous awards in recognition of her contributions to neuroscience and psychiatric research:

  • 2005 & 2007 – NARSAD Young Investigator Award, Brain & Behavior Research Foundation (formerly National Alliance for Research on Schizophrenia & Depression).[27][28]
  • 2008 – Neuroscience of Brain Disorders Award, McKnight Foundation[29]
  • 2009 – Honorable Mention, Daniel X. Freedman Award for Outstanding Basic Research[27][28]
  • 2011 – Rising Star Award, International Mental Health Research Organization[30][31]
  • 2015 – Elected Fellow, American College of Neuropsychopharmacology[32]
  • 2016 – NARSAD Independent Investigator Award, Brain & Behavior Research Foundation[27][31]
  • 2019 – Outstanding Mentorship Award by the Psychiatry Department
  • 2021 – Colvin Prize for Outstanding Achievement in Mood Disorders Research, Brain & Behavior Research Foundation[33][34]

Professional Affiliations

Colleen McClung is a member of various neuroscience societies through which she has contributed her expertise and research from psychiatry and circadian rhythms:

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Selected publications


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References

External links

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