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From stress to anhedonia: examining inflammation and altered glutamate function as distinct or common etiological pathways

Award Number: K01MH126308
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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From stress to anhedonia: examining inflammation and altered glutamate function as distinct or common etiological pathways - Anhedonia is a common transdiagnostic symptom that frequently fails to respond to available psychosocial and pharmacological treatments and has been linked to disability and suicidal risk. Development of new treatments for anhedonia has been hindered by its substantial heterogeneity. To address this problem, the NIMH Research Domain Criteria (RDoC) approach has emphasized the need to identify circuit-specific sub-domains of functional impairment. One potential pathway to anhedonic symptoms is through neurobiological changes associated with prolonged exposure to stress (“stress-induced anhedonia”), characterized neurally by reduced activation in reward-related regions such as the medial prefrontal cortex (mPFC) and ventral striatum, and behaviorally by a failure to pursue rewards and reduced ability to anticipate positive or rewarding outcomes (i.e. pessimistic biases). While the specific mechanisms by which elevated stress may lead to anhedonia are not fully understood, two candidate mechanisms are elevated inflammatory cytokines and altered glutamatergic functioning. Stressors are known to increase glutamate, particularly in mPFC, leading to numerous negative effects including excito-toxicity, shrinkage of dendrites, and reduction of spine synapse density. Stressors have also been shown to activate immune responses, elevating proinflammatory cytokine tumor necrosis factor (TNF) alpha, interleukin-6 (IL-6), and IL-1b. Critically, a growing body of work has suggested that elevated inflammation and altered glutamate functioning may be linked. The goal of the current proposal is therefore to explore the independent and additive contributions of inflammation and glutamatergic functioning to the experience of pessimistic expectations in stress-induced anhedonia. We propose to employ plasma analysis of peripheral inflammatory markers and MRS glutamate in 40 healthy control participants without anhedonia and 60 participants with anhedonia stratified by level of peripheral inflammation. In Aim 1 we will analyze associations between perceived stress, inflammation, and an ecological momentary assessment (EMA) measure of pessimistic expectations. In Aim 2, we will use an acute stress manipulation and MR spectroscopy to examine changes in mPFC glutamate in response to acute stress, examining associations between perceived stress, glutamatergic response to stress, and pessimistic expectations. Finally, in Aim 3 we will examine whether glutamatergic response to stress is related to individual differences in inflammation and will test a serial mediation model of inflammation and glutamate response to stress on pessimistic expectations. This work will provide insight into the neurobiological mechanisms that underlie stress-induced anhedonia and the results will be used to inform future work using targeted treatments.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $180,068 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	4	3/12/2025	NON-COMPETING CONTINUATION	$180,068
														Subtotal = $180,068

Issue Date FY: 2024 ( Subtotal = $180,068 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	3	3/1/2024	NON-COMPETING CONTINUATION	$180,068
														Subtotal = $180,068

Issue Date FY: 2023 ( Subtotal = $180,068 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	2	5/3/2023	NON-COMPETING CONTINUATION	$180,068
														Subtotal = $180,068

Issue Date FY: 2022 ( Subtotal = $180,068 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	1	3/22/2022	NEW	$180,068
														Subtotal = $180,068

Grand Total All Awards = $720,272

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From stress to anhedonia: examining inflammation and altered glutamate function as distinct or common etiological pathways

Award Number: K01MH126308

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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