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Workshop: "Neurobiological Basis of Circadian Rhythms Interaction with Complex Behavior"

Meeting Summary
Bethesda, Maryland

Sponsored by:
National Institute of Mental Health

The overall goal of this workshop was to encourage and further extend research on the neurobiological mechanisms that underlie the association between circadian rhythms with higher brain functions and behaviors of importance to the NIMH research mission. The circadian clock controls a vast number of physiological variables, and disruptions of circadian rhythms have been implicated in psychiatric disorders.  The rich progress in understanding both molecular circadian mechanism and behavioral circadian phenomenon, indicate that the field is now poised for a deeper and more mechanistic understanding of how circadian oscillators interact with brain circuits and neurotransmitter systems to influence diverse processes including emotion, cognition and social interactions. NIMH convened this multidisciplinary workshop to bring together some of the leading investigators in this area to: (a) assess current research findings and identify important questions relevant to the neurobiology of the interactions between circadian oscillators and the neural circuits implicated in higher brain function and behaviors, (b) evaluate how the most promising approaches could improve the understanding of how circadian rhythms regulate brain function and behavior under normal and pathological conditions, (c) identify current gap areas and challenges to advancing knowledge of how disruptions in circadian rhythms and sleep may increase vulnerability for psychiatric disorders and (d) discuss strategies to facilitate the translation of basic science discoveries in circadian biology to clinical settings in order to prevent or delay onset of mental illnesses, design diagnostic tools and propose new therapeutic strategies for mental illnesses.

The presentations explored several research topics and covered a wide range of novel findings and ideas under five major themes including:  (1) impact of molecular clocks on physiology and behavior; (2) interactions between circadian signals and cognitive functions; (3) interface of circadian rhythms with sleep and its relevance to normal and abnormal behaviors; (4) the clinical perspective on the relationship between circadian rhythm abnormalities and affective disorders and (5) animal models of circadian rhythm abnormalities and mood disorders.

Workshop participants identified several research areas needed to advance understanding of how disruptions in circadian rhythms might be linked to psychiatric disorders. A big gap area exists between circuits and behavior. Participants commented that the field needs a better understanding of how the suprachiasmatic nucleus– SCN, which contains core clock machinery, integrates with other brain circuits. Another gap area is how SCN coupling rescues rhythms and behaviors including learning and memory, affect, anxiety, social and motivational behaviors. For instance, increasing evidence indicates the importance of examining interactions between the CLOCK genes and monoaminergic neurotransmitter circuits as these interactions may play an important role in regulating cognitive processes, affect and sleep.

Another promising area is the further exploration of peripheral system markers that may reflect disturbances in brain circadian rhythms and behavior. For instance, cultured fibroblasts demonstrate sustained and robust rhythms, indicating their potential utility as a model for neuronal circadian rhythms. These observations suggest that fibroblasts have the translational potential to serve as peripheral markers for disturbances in circadian rhythms in psychiatric disorders. Concurrent studies of circadian rhythms of fibroblasts and genetic polymorphisms related to circadian control may facilitate comparison between individuals with bipolar disorder and those at risk for the illness.

Participants encouraged more research on how the circadian clock may control metabolism at the level of individual cells and how mitochondrial pathways may be involved in energy utilization and synaptic plasticity in neurons. If circadian rhythms function through these metabolic cycles, building bridges between fundamental genetics and cell biology can increase understanding of how altered systems and behaviors that occur during transitional phases of development may lead to developmental disorders. Likewise, understanding the type of brain plasticity that governs transitions between phasic (i.e., steady state) activity of the system versus tonic (i.e, higher state activity when a system acquires a lot of information) may help explain shifts between normative versus perturbed systems.

Participants discussed gap areas in developing appropriate animal models to study the link between circadian rhythms and behaviors. For example, the field needs to develop animal models with better face validity and more steady rhythm patterns. Other examples are animal models of (1) seasonal behavior, (2) temporal disorganization in adolescence and, (3) vulnerability and protective factors in circadian rhythm disturbances in adolescence. Participants also emphasized the need for more studies in female animal models in order to increase knowledge of how sex differences in circadian rhythms and sleep may mediate sex/gender specific differences in the expression of psychiatric disorders. This work, combined with further research on genetically altered animal models should increase knowledge of the mechanisms that mediate circadian processes and the role of CLOCK machinery in the association between disturbed circadian rhythms and mood disorders.

The participants suggested that more basic science studies are needed to clarify the interaction between seasonal factors and homeostatic and circadian mechanisms as these are likely to play a role in many complex behaviors. Longitudinal human studies should help to elucidate phenotypes, correlate phenotypes with genotypes and determine how genotype/phenotype interactions influence seasonal patterns of behavior. These suggestions also indicate the importance of determining the mechanisms underlying the CLOCK genes interactions with species–typical environments to understand the complex relationships between genetics, environmental factors, chronotypes, and psychiatric illnesses. Understanding these factors should facilitate development of circadian rhythm/sleep– specific physiological markers that can be applied toward methods for identify high levels of risk and preventing mental illnesses.

In summary, participants identified several important questions, strengths and gap areas relevant to research on the neurobiological underpinnings of the circadian rhythms interaction with higher brain function and behaviors. The rich dialogue between clinical and basic scientists created tangible new research directions and identified promising strategies for expanding basic, translational, and clinical studies on circadian rhythms to help bridge the gaps between genes, circuits and behavior. The goals and the products of this workshop address the NIMH’s Strategic Plan, Objective 1 to promote discovery in the brain and behavioral sciences to fuel research on the causes of mental disorders, and Objective 2 to chart mental illness trajectories to determine when, where and how to intervene.

For more information, please contact Dr. Aleksandra Vicentic at vicentica@mail.nih.gov.