Exercise and Movement-Triggered Anxiety Relief

Post by Baldomero B. Ramirez Cantu

The takeaway

This study elucidates the role of a previously unidentified neural circuit involving the cerebellum, amygdala, and hypothalamus in driving the anxiolytic effects of exercise. 

What's the science?

Anxiety disorders constitute a spectrum of mental health conditions marked by enduring sensations of fear, apprehension, or discomfort. Exercise is hailed as a first-line and often successful intervention for managing anxiety symptoms. Despite the well-documented relationship between physical activity and anxiety reduction, the exact neural mechanisms underlying exercise's impact on anxiety remain incompletely understood.

The amygdala and hypothalamus are known to be key nodes in the brain's "anxiety circuitry”, contributing to the manifestation and regulation of anxiety-like behaviors. However, a much less explored brain region in this context is the cerebellum, a region primarily associated with motor function. Advancing our understanding of the interaction between anxiety and motor-associated brain regions could offer significant insights into how exercise modulates anxiety. This week, Zhang, Wu, Shen, Ji, et al. published a study in Neuron that investigates the functional connectivity among the cerebellum, amygdala, and hypothalamus in the context of exercise-induced anxiety relief, and provides one of the first pieces of direct evidence of cerebellar involvement in anxiety modulation. 

How did they do it?

First, functional magnetic resonance imaging (fMRI) data were collected from humans to assess the functional connectivity between the cerebellum and amygdala as it relates to anxiety. This human study served as a starting point, establishing a relationship between the cerebellar-amygdala circuit and anxiety. Next, to study this circuitry with greater precision and understand the specific subregions and cell types involved in the exercise-induced amelioration of anxiety, the authors performed experiments in rats as model organisms.

Viral mediated tracing techniques, including anterograde and retrograde tracer injections, were used to map the direct projections from the dentate nucleus of the cerebellum to the central lateral amygdala. These experiments aimed to delineate the anatomical connectivity between cerebellar nuclei and amygdalar subregions, shedding light on the structural basis of cerebello-amygdalar circuitry involved in anxiety regulation. Viral tracing experiments were also performed in order to map the connectivity between the DN and orexin-expressing neurons in the perifornical area of the hypothalamus. The authors conducted fMRI scans on anesthetized rats to investigate the cerebellar-amygdala circuitry's functional connectivity between rats subjected to exercise and controls. 

Finally, optogenetic and chemogenetic manipulations were employed in rats subjected to anxiety assays following rotarod running to elucidate the impact of motor activity on anxiety levels. These manipulations allowed researchers to selectively activate or inhibit cerebellar nuclei neurons projecting to the amygdala, providing insights into the causal relationship between cerebello-amygdalar circuitry and anxiety symptoms.

What did they find?

First, the researchers observed anxiety was negatively correlated with cerebello-amygdalar functional connectivity in humans. Next, they found reduced anxiety levels in rats subjected to rotarod running. For example, an increased preference for open arms in maze tests was observed (indicating an anxiety reduction), demonstrating that exercise had similar effects on the anxiety responses of rats and humans. Notably, functional connectivity analyses of rat fMRI scans revealed enhanced connectivity between the cerebellar nuclei and amygdala following motor activity.

They identified a direct cerebello-amygdalar projection, particularly from the dentate nucleus to the central lateral amygdala, suggesting a structural basis for regulation of anxiety-like emotions. Optogenetic and chemogenetic manipulations demonstrated that activation of cerebello-amygdalar projections significantly reduced anxiety-like behaviors in rats, while inhibition of this pathway attenuated the anxiolytic effects of exercise. Additionally, the researchers uncovered orexinergic hypothalamo-cerebellar projections as crucial components in anxiety regulation, particularly during challenging exercises. Activation of orexinergic neurons in the perifornical area of the hypothalamus alleviated stress-induced anxiety, highlighting the role of hypothalamo-cerebellar circuits in modulating anxiety behavior.

What's the impact?

This study significantly advances our understanding of the neural circuitry underlying anxiety regulation, particularly highlighting the previously unknown intricate interplay between the cerebellum, amygdala, and hypothalamus. This information is invaluable to our advancement of treatments and interventions for anxiety disorders.

Access the original scientific publication here.

Biomarkers for Diagnosing Alzheimer’s Disease in the Indigenous Population

Post by Soumilee Chaudhuri

The takeaway

This study reveals unique patterns of blood-based clues linked to Alzheimer’s Disease (AD) in older American Indian (AI) individuals — a critically understudied population in healthcare and biomedical science. Blood-based biomarkers in this population suggest early and more widespread presence of AD-related changes in this indigenous cohort, compared to other ethnic groups.

What's the science?

Alzheimer’s Disease (AD) is the most common form of dementia and affects over ~6.5 million people in the United States. As a major public health concern, early identification of AD is important for effective prevention and treatment strategies for this debilitating disorder. However, existing methods of diagnosis such as cerebrospinal fluid (CSF) analysis and positron emission tomography (PET) imaging are invasive, expensive, and unaffordable for minoritized populations, including American Indians for whom treatment is often inaccessible due to socioeconomic and systemic factors. Therefore, there is a critical need for noninvasive and low-cost biomarkers that can accurately detect AD pathology, particularly in these underserved communities. The Strong Heart Study (SHS) addresses this gap by investigating blood biomarkers related to AD in a cohort of older American Indian individuals recruited from designated field centers in Arizona, North & South Dakota, and Oklahoma. By examining associations between these biomarkers and clinical, imaging, and cognitive findings, the authors provide critical insights into AD characteristics, diagnostics, and risk factors specific to the American Indian elderly population.

How did they do it?

Initially, SHS recruited American Indian adults aged 64-94 years old from tribal lands in the US Northern Plains, Southern Plains, and Southwest starting in 1981-1991; thereafter, the survivors of this initial cohort were recruited for cognitive aging and AD studies in 2010 ( N = 818) and invited back for a second visit in 2017 (N = 403). Five blood biomarkers of AD including phosphorylated tau (ptau), amyloid beta (A), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were obtained from all participants using designated research platforms. Participants also underwent magnetic resonance imaging (MRI) and neuropsychological & cognitive testing (such as memory, executive function, simple and divided attention, etc.). Researchers used statistical methods such as regression analyses and Receiver Operator Characteristics (ROC) to assess the relationships between these blood biomarkers and various imaging measures and cognitive outcomes.

What did they find?

The researchers found significant differences in blood biomarker levels related to AD pathology among the SHS cohort of older American Indian individuals compared to other ethnic groups. The levels of normal Amyloid beta (A) — the lack of which is a hallmark of AD pathology — were significantly lower in this cohort compared to non-Hispanic white (NHW), African American (AA), and Hispanic/Latino populations, indicating a greater degree (almost 3 times) of pathology in this cohort compared to other populations. However, the levels of GFAP and NfL — other biomarkers of AD — were similar in this American Indian cohort as compared to other age-comparable populations. Associations were observed between blood biomarker levels of AD and MRI and cognitive test scores, suggesting potential implications for AD diagnosis and risk assessment in this population. Taken together, these findings reflect that previous studies of comparable risk between American Indian and non-Hispanic White individuals may underestimate AD prevalence in American Indians.

What's the impact?

This is the first study to investigate blood biomarkers for Alzheimer’s Disease in a population historically underrepresented in research: American Indians or the Indigenous people. These findings highlight the importance of understanding cognition and aging in diverse populations facing healthcare disparities so as to improve diagnosis and craft efficient, non-invasive, and affordable treatment strategies. It also shows us that previous studies have severely underestimated the risk of AD in this vulnerable population and urges us to be mindful of recruiting diverse participants from all demographics in AD studies so as to tailor diagnosis and treatment strategies to all.  

Access the original scientific publication here

How Does the Endocannabinoid System Reduce Chronic Pain Following Injury?

Post by Lani Cupo

The takeaway

Neuropathic pain can result from an injury or disease, and has been related to disruptions in circadian rhythms. Evidence suggests a novel link between circadian rhythms, the endocannabinoid system, and neuropathic pain. 

What's the science?

Prior evidence suggests disruption to circadian rhythms can increase sensitivity to neuropathic pain, however, the role of the underlying genes and proteins that control the circadian rhythms (clock genes) is still poorly understood. This week in PNAS Nexus, Yamakawa and colleagues use mouse models to investigate the role of the clock genes in the development of neuropathic pain, finding a previously undocumented role of the clock genes in neuropathic pain and a link with the endocannabinoid system.

How did they do it?

The authors performed a set of experiments in mouse models to investigate the role of a specific protein known as period2 (Per2 - integral in regulating circadian rhythms) in the development of neuropathic pain. To induce neuropathic pain in the mice, the authors used a well-established model involving the ligation (or clamping) of part of the sciatic nerve in the hind limb of an animal, producing chronic pain that can be measured with tests for pain sensitivity. First, the authors performed the operation in control mice as well as those lacking the protein Per2 and examined whether mice without Per2 still developed hypersensitivity to pain. Additionally, they examined the quantity and form of glial cells following the injury.

To examine what receptors were involved in neuropathic pain, the authors injected a series of compounds that blocked specific receptors in turn and examined the pain response; if the pain response was absent when a certain receptor was blocked, they would know it was key in hypersensitivity to pain. Next, the authors sought compounds whose production was controlled by binding the identified receptors, as well as cells that produced these compounds. Finally, they examined whether increasing expression of these receptors in mice with functioning Per2 protein reduces the neuropathic pain response.

What did they find?

First, the authors were surprised to find that in mice without Per2, there was no evidence of hypersensitivity to pain. They had expected that the Per2 protein was involved in fluctuations of pain sensitivity over the day, however, their results indicate Per2 is actually involved in the development of pain sensitization in general. While pain hypersensitivity was absent in mice lacking Per2, the authors observed alterations in glial cells in mice both with and without Per2, suggesting the lack of Per2 did not prevent changes in this molecular mechanism. 

Next, the authors identified a specific type of adrenergic receptor (α1-AR) involved in the lack of pain hypersensitization in mice without Per2. This receptor is part of a superfamily (G-protein coupled receptors) that, when activated, act as messengers by producing other compounds in a cell. In this case, the authors found that in mice without Per2, an endocannabinoid, 2-AG, was increased, with its production modulated by activation of α1-AR. Specifically, they found Per2 alters the expression of these receptors and the levels of 2-AG produced by astrocytes in the spinal cord. So, in summary, disrupting circadian rhythms by altering the protein Per2 altered a specific receptor in astrocytes which changes the expression of an endocannabinoid, 2-AG, and reduces pain hypersensitivity.  

What's the impact?

This study describes a new role of the circadian clock proteins and the endocannabinoid system in the development of neuropathic pain. The results increase the understanding of how disruptions in sleep cycles may impact neuropathic pain and may, in time, lead to new forms of treatment.

Access the original scientific publication here.