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I have broad interests in understanding the interactions between the nervous and immune systems, particularly with respect to alterations in behavior and cognitive functioning. It has only recently been appreciated that the nervous system and immune system communicate and influence one another. It is now recognized that products (e.g. cytokines) released by immune cells alter brain-mediated responses (e.g. behavioral, hormonal, and cognitive processes). For example, in response to foreign microorganisms cytokines are released by immune cells and stimulate brain-mediated physiological and behavioral responses, which are commonly referred to as sickness responses (e.g. fever, decreasing appetite, increasing sleep, amplifying pain, altering hormone levels, and impairing cognitive processes). 

Brain cytokine levels also increase when an organism is exposed to stressful events, during normal aging and during neurodegenerative diseases. It has been proposed that elevated brain cytokines mediate some of the behavioral, cognitive, and emotional changes that are associated with these times. My laboratory is interested in understanding the regulation of brain cytokines, what role brain cytokines play in mediated various physiological/behavioral responses, and how the regulation of brain cytokines changes with repeated stressor exposure.

Recent Abstracts

Sex Differences in the Regulation of Brain IL-1b in Response to Chronic Stress

David F. Barnard, Kristin M. Gabella, Adam C. Kulp, Austin D. Parker, Patrick B. Dugan, John D. Johnson

Elevations in brain interleukin-1 beta (IL-1b) during chronic stress exposure have been implicated in behavioral and cognitive impairments associated with depression and anxiety. Two critical regulators of brain IL-1b production during times of stress are glucocorticoids and catecholamines. These hormones work in opposition to one another to inhibit (via glucocorticoid receptors) or stimulate (via beta-adrenergic receptors: b-AR) IL-1b production. While chronic stress often heightens both corticosterone and catecholamine levels, it remains unknown as to how chronic stress may affect the “yin-yang” balance between adrenergic stimulation and glucocorticoid suppression of brain IL-1b.  To investigate this further, male and female rats underwent 4 days of stress exposure or served as non-stressed controls. On day 5, animals were administered propranolol (b-AR antagonist), metyrapone (a glucocorticoid synthesis inhibitor), vehicle, or both drugs and brain IL-1b mRNA was measured by rtPCR in limbic brain areas. In males, administration of propranolol had no effect on IL-1b expression in non-stressed controls but significantly reduced IL-1b in the hippocampus and amygdala of chronically stressed animals. In females, propranolol significantly reduced IL-1b in the amygdala and hypothalamus of both control and stressed rats. In male rats, metyrapone treatment significantly increased IL-1b mRNA regardless of stress treatment in all brain areas, while in female rats metyrapone only increased IL-1b in the hypothalamus. Interestingly, propranolol treatment blocked the metyrapone-induced increase in brain IL-1b indicating the increase in brain IL-1b following metyrapone treatment was due to increase b-AR activation. Additional studies revealed that metyrapone significantly increases norepinephrine turnover in the hypothalamus and medial prefrontal cortex in male rats and that microglia appear to be the cell type contributing to the production of IL-1b. Overall, data reveal that stress exposure in male rats affects the regulation of brain IL-1b by the norepinephrine-b-AR pathway, while stress had no effect in the regulation of brain IL-1b in female rats.

Sympathetic Nervous System Contributes to Enhanced Corticosterone Levels Following Chronic Stress

Steven A. Lowrance, Amy Ionadi, Erin McKay, Xavier Douglas, and John D. Johnson

Exposure to chronic stress often elevates basal circulating glucocorticoids during the circadian nadir and leads to exaggerated glucocorticoid production following exposure to subsequent stressors.  While glucocorticoid production is primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis, there is evidence that the sympathetic nervous system can affect diurnal glucocorticoid production by direct actions at the adrenal gland.  Experiments here were designed to examine the role of the HPA and sympathetic nervous system in enhancing corticosterone production following chronic stress.  Rats were exposed to a four-day stress paradigm or control conditions then exposed to acute restraint stress on the fifth day to examine corticosterone and ACTH responses.  Repeated stressor exposure resulted in a small increase in corticosterone, but not ACTH, during the circadian nadir, and also resulted in exaggerated corticosterone production 5, 10, and 20min following restraint stress.  While circulating ACTH levels increased after 5min of restraint, levels were not greater in chronic stress animals compared to controls until following 20min.  Administration of astressin (a CRH antagonist) prior to restraint stress significantly reduced ACTH responses but did not prevent the sensitized corticosterone response in chronic stress animals.  In contrast, administration of chlorisondamine (a ganglionic blocker) returned basal corticosterone levels in chronic stress animals to normal levels and reduced early corticosterone production following restraint (up to 10min) but did not block the exaggerated corticosterone response in chronic stress animals at 20min.  These data indicate that increased sympathetic nervous system tone contributes to elevated basal and rapid glucocorticoid production following chronic stress, but HPA responses likely mediate peak corticosterone responses to stressors of longer duration.

Recent Publications

Beals, N., Mohamed, F., Prakash, K., Johnson, J.D., Basu, S. Rationally designed DNA therapeutics can modulate human tyrosine hydroxylase expression by controlling specific G-quadruplex formation in its promoter. Molecular Therapy (in press). DOI: 10.1016/j.ymthe.2021.05.013

Kulp, A., Lowden, B., Chaudhari, S., Ridley, C., Krzoska, J., Barnard, D., Mehta, D., Johnson, J.D. Exaggerated corticosterone responses observed do not mediate the enhanced fear memories in chronic stress rats. Behavioural Brain Research (2020) 382:112480. 

Johnson, J.D., Barnard, D.F., Kulp, A.C., Mehta, D.M. Neuroendocrine regulation of brain cytokines after psychological stress. Journal of the Endocrine Society (2019) May 14;3(7):1302-1320 (invited review). 

Barnard, D.F., Gabella, K.M., Kulp, A.C., Parker, A.D., Dugan, P.B., Johnson, J.D.  Sex Differences in the Regulation of Brain IL-1 in Response to Chronic Stress. Psychoneuroendocrinology (2019) Jan 25 103:203-211 

Johnson, J.D. Use of the flu vaccine opens the door to studying associations between inflammation, depression, and cognitive impairments Brain, Behavior, and Immunity (2018) May 70:5

Lowrance, S., Ionadi, A., McKay, E., Douglas, X., and Johnson, J.D.  Sympathetic Nervous System Contributes to Enhanced Corticosterone Levels Following Chronic Stress. Psychoneuroendocrinology (2016) 68:163-170.

Camp, R. and Johnson, J.D.  Repeated stressor exposure enhances contextual fear memory in a beta-adrenergic receptor-dependent process and increases impulsivity in a non-beta receptor-dependent fashion.  Physiology & Behavior (2015) 150:64-68.

Remus, J., Stewart, L., Camp, R., Novak, C., and Johnson, J.D.  Interaction of Metabolic Stress with Chronic Mild Stress in Altering Brain Cytokines and Sucrose Preference.  Behavioral Neuroscience (2015) 129(3):321-30.

Johnson, J.D., Zimomra, Z.R., Stewart, L.T.  Beta-Adrenergic Receptor Activation Primes Microglia Cytokine Production.  Journal of Neuroimmunology (2013) 254:161-164.

Porterfield, V.M., Gabella, K.M., Simmons, M.A., Johnson, J.D.  Repeated Stressor Exposure Regionally Enhances Beta-Adrenergic Receptor Mediated Brain IL-1b Production.

Brain, Behavior, and Immunity (2012) 26:1249-1255.

Recent Grants

“Role of Microglia and IL-1 in Stress-Induced Enhancement of Aversive Memories”

Principle Investigator: John D. Johnson (95%)          Co-I: Jasnow (5%)

Agency: National Institutes of Health (1 R15 MH114049-01 A1)

Award Total: $450,000

Funding period: 6/1/18-5/31/22

“Stress-Induced Noradrenergic Dysregulation of Neuroinflammation and HPA Responses”

Principle Investigator: John D. Johnson

Agency: National Institute of Mental Health (1R15 MH099580-01A1)

Award Total: $441,600

Funding period 7/1/13-6/30/17

“Targeting Stress Resilience Without Detriment to Adaptive Stress Response”

Principle Investigator: John D. Johnson

Agency: DARPA-Department of Defense

Award Total: $300,000

Funding period 5/28/10-5/27/13

Courses Taught

• Career Pathways in Biology

• Foundation of Neuroscience