Ryan J . Worthen, PhD | University of Miami Miller School of Medicine (original) (raw)

Papers by Ryan J . Worthen, PhD

Neurobiology of Disease, 2022

Postpartum depression (PPD) is the most common psychiatric complication associated with pregnancy... more Postpartum depression (PPD) is the most common psychiatric complication associated with pregnancy and childbirth with debilitating symptoms that negatively impact the quality of life of the mother as well as inflict potentially long-lasting developmental impairments to the child. Much of the theoretical pathophysiology put forth to explain the emergence of PPD overlaps with that of major depressive disorder (MDD) and, although not conventionally described in such terms, can be seen as neurodegenerative in nature. Framing the disorder from the perspective of the well-established inflammatory theory of depression, symptoms are thought to be driven by dysregulation, and subsequent hyperactivation of the body's immune response to stress. Compounded by physiological stressors such as drastic fluctuations in hormone signaling, physical and psychosocial stressors placed upon new mothers lay bare a number of significant vulnerabilities, or points of potential failure, in systems critical for maintaining healthy brain function. The inability to compensate or properly adapt to meet the changing demands placed upon these systems has the potential to damage neurons, hinder neuronal growth and repair, and disrupt neuronal circuit integrity such that essential functional outputs like mood and cognition are altered. The impact of this deterioration in brain function, which includes depressive symptoms, extends to the child who relies on the mother for critical life-sustaining care as well as important cognitive stimulation, accentuating the need for further research.

Journal of Neuroinflammation, 2020

Background: Major depressive disorder is a widespread mood disorder. One of the most debilitating... more Background: Major depressive disorder is a widespread mood disorder. One of the most debilitating symptoms patients often experience is cognitive impairment. Recent findings suggest that inflammation is associated with depression and impaired cognition. Pro-inflammatory cytokines are elevated in the blood of depressed patients and impair learning and memory processes, suggesting that an anti-inflammatory approach might be beneficial for both depression and cognition. Methods: We subjected mice to the learned helplessness paradigm and evaluated novel object recognition and spatial memory. Mice were treated with IL-10 intranasally or/and microglia cells were depleted using PLX5622. Statistical differences were tested using ANOVA or t tests. Results: We first established a mouse model of depression in which learning and memory are impaired. We found that learned helplessness (LH) impairs novel object recognition (NOR) and spatial working memory. LH mice also exhibit reduced hippocampal dendritic spine density and increased microglial activation compared to non-shocked (NS) mice or mice that were subjected to the learned helpless paradigm but did not exhibit learned helplessness (non-learned helpless or NLH). These effects are mediated by microglia, as treatment with PLX5622, which depletes microglia, restores learning and memory and hippocampal dendritic spine density in LH mice. However, PLX5622 also impairs learning and memory and reduces hippocampal dendritic spine density in NLH mice, suggesting that microglia in NLH mice produce molecules that promote learning and memory. We found that microglial interleukin (IL)-10 levels are reduced in LH mice, and IL-10 administration is sufficient to restore NOR, spatial working memory, and hippocampal dendritic spine density in LH mice, and in NLH mice treated with PLX5622 consistent with a pro-cognitive role for IL-10.

Neuroscience Research, 2018

Insulin-like growth factor 2 (IGF2) is abundantly expressed in the central nervous system (CNS). ... more Insulin-like growth factor 2 (IGF2) is abundantly expressed in the central nervous system (CNS). Recent evidence highlights the role of IGF2 in the brain, sustained by data showing its alterations as a common feature across a variety of psychiatric and neurological disorders. Previous studies emphasize the potential role of IGF2 in psychiatric and neurological conditions as well as in memory impairments, targeting IGF2 as a pro-cognitive agent. New research on animal models supports that upcoming investigations should explore IGF2 s strong promising role as a memory enhancer. The lack of effective treatments for cognitive disturbances as a result of psychiatric diseases lead to further explore IGF2 as a promising target for the development of new pharmacology for the treatment of memory dysfunctions. In this review, we aim at gathering all recent relevant studies and findings on the role of IGF2 in the development of psychiatric diseases that occur with cognitive problems.

Frontiers in Neuroscience, 2018

Major depressive disorder (MDD) is a prevalent and debilitating disorder, often fatal. Treatment ... more Major depressive disorder (MDD) is a prevalent and debilitating disorder, often fatal. Treatment options are few and often do not provide immediate relief to the patients. The increasing involvement of inflammation in the pathology of MDD has provided new potential therapeutic avenues. Cytokine levels are elevated in the blood and cerebrospinal fluid of MDD patients whereas immune cells often exhibit an immunosuppressed phenotype in MDD patients. Blocking cytokine actions in patients exhibiting MDD show some antidepressant efficacy. However, the role of cytokines, and the immune response in MDD patients remain to be determined. We reviewed here the roles of the innate and adaptive immune systems in MDD, as well as potential mechanisms whereby the immune response might be regulated in MDD.

Brain, Behavior, and Immunity, 2018

Recovery from major depressive disorder is difficult, particularly in patients who are refractory... more Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5. Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3. In non-recovered mice with prolonged learned helpless, stimulation of sphingosine 1-phosphate receptors by Fingolimod or administration of the TNFα inhibitor etanercept repaired the BBB and reversed impaired recovery from prolonged learned helplessness. Thus, disrupted BBB integrity mediated in part by TNFα contributes to blocking recovery from prolonged learned helplessness depression-like behavior. Overall, this report describes a new model of prolonged depression-like behavior and demonstrates that stress-induced GSK3 activation contributes to disruption of BBB integrity a Corresponding author: Richard S. Jope, Miller

Trends in Biochemical Sciences, 2017

Psychological stress has a pervasive influence on our lives. In many cases adapting to stress str... more Psychological stress has a pervasive influence on our lives. In many cases adapting to stress strengthens organisms, but chronic or severe stress is usually harmful. One surprising outcome of psychological stress is activation of an inflammatory response, resembling inflammation caused by infection or trauma. Excessive psychological stress and the consequential inflammation in the brain can increase susceptibility to psychiatric diseases, such as depression, and impair learning and memory, including in some patients with cognitive deficits. An emerging target to control detrimental outcomes of stress and inflammation is glycogen synthase kinase-3 (GSK3). GSK3 promotes inflammation, partly by regulating key transcription factors in the inflammation signaling pathway, and GSK3 can impair learning by promoting inflammation and by inhibiting long term potentiation (LTP). Drugs inhibiting GSK3 may prove beneficial for controlling mood and cognitive impairments caused by excessive stress and the associated neuroinflammation. Excessive stress and inflammation are detrimental to health Stress and inflammation are normal processes that help organisms respond and adapt to changes in the environment, to trauma, and to infection (see Glossary). In this article we focus on psychological stress and the ensuing inflammation in the brain (neuroinflammation). If these are severe or prolonged, they are usually detrimental, often leading to a variety of medical problems or worsening of pre-existing health problems. The deleterious effects of psychological stress and inflammation can impact many organs and diseases, including cardiovascular diseases, cancers, and immunological diseases. However, here we focus on how psychological stress and neuroinflammation impact the regulation of mood and cognition.

Psychoneuroendocrinology, 2016

PLoS ONE, 2010

Organisms must utilize multiple mechanisms to maintain energetic homeostasis in the face of limit... more Organisms must utilize multiple mechanisms to maintain energetic homeostasis in the face of limited nutrient availability. One mechanism involves activation of the heterotrimeric AMP-activated protein kinase (AMPK), a cell-autonomous sensor to energetic changes regulated by ATP to AMP ratios. We examined the phenotypic consequences of reduced AMPK function, both through RNAi knockdown of the gamma subunit (AMPKc) and through expression of a dominant negative alpha (AMPKa) variant in Drosophila melanogaster. Reduced AMPK signaling leads to hypersensitivity to starvation conditions as measured by lifespan and locomotor activity. Locomotor levels in flies with reduced AMPK function were lower during unstressed conditions, but starvation-induced hyperactivity, an adaptive response to encourage foraging, was significantly higher than in wild type. Unexpectedly, total dietary intake was greater in animals with reduced AMPK function yet total triglyceride levels were lower. AMPK mutant animals displayed starvation-like lipid accumulation patterns in metabolically key liver-like cells, oenocytes, even under fed conditions, consistent with a persistent starved state. Measurements of O 2 consumption reveal that metabolic rates are greater in animals with reduced AMPK function. Lastly, rapamycin treatment tempers the starvation sensitivity and lethality associated with reduced AMPK function. Collectively, these results are consistent with models that AMPK shifts energy usage away from expenditures into a conservation mode during nutrient-limited conditions at a cellular level. The highly conserved AMPK subunits throughout the Metazoa, suggest such findings may provide significant insight for pharmaceutical strategies to manipulate AMPK function in humans.

PLoS ONE, 2008

Background: Neurons require precise cytoskeletal regulation within neurites, containing microtubu... more Background: Neurons require precise cytoskeletal regulation within neurites, containing microtubule tracks for cargo transport in axons and dendrites or within synapses containing organized actin. Due to the unique architecture and specialized function of neurons, neurons are particularly susceptible to perturbation of the cytoskeleton. Numerous actin-binding proteins help maintain proper cytoskeletal regulation.

Dissertation by Ryan J . Worthen, PhD

Scholarship@Miami, Dec 2020

Major depressive disorder is a widespread mood disorder. One of the most debilitating symptoms pa... more Major depressive disorder is a widespread mood disorder. One of the most debilitating symptoms patients often experience is cognitive impairment. Recent findings suggest that inflammation is associated with depression and impaired cognition. Pro-inflammatory cytokines are elevated in the blood of depressed patients and impair learning and memory processes, suggesting that an anti-inflammatory approach might be beneficial for both depression and cognition. Utilizing the learned helplessness paradigm, we first established a mouse model of depression in which learning and memory are impaired. We found that learned helplessness (LH) impaired novel object recognition (NOR) and spatial working memory. LH mice also exhibited reduced hippocampal dendritic spine density and increased microglial activation compared to non-shocked (NS) mice or mice that were subjected to the learned helpless paradigm but did not exhibit learned helplessness (non-learned helpless, or NLH). These effects were mediated by microglia, as treatment with PLX5622, which depletes microglia and macrophages, restored learning and memory and hippocampal dendritic spine density in LH mice. However, PLX5622 also impaired learning and memory and reduced hippocampal dendritic spine density in NLH mice, suggesting that microglia in NLH mice are involved in the production of molecules that promote learning and memory. We found that microglial interleukin (IL)-10 levels were reduced in LH mice and IL-10 administration was sufficient to restore NOR, spatial working memory, and hippocampal dendritic spine density in LH mice, and in NLH mice treated with PLX5622, consistent with a pro-cognitive role for IL-10. Altogether, these data demonstrate the critical role of IL-10 in promoting learning and memory after learned helplessness.