NOTE: End date changed to 01/11/2023 per L. Juliette/JSC (Ed., 3/20/23)

NOTE: End date changed to 09/30/2025 per L. Juliette/JSC (Ed., 5/7/22)

The central hypothesis of this proposal is that there is a synergistic effect of multiple factors (defined by GCRsim, isolation confinement stress, and altered gravity) encountered in deep space exposure that leads to enhanced inflammatory response, promotes synapse loss, and decreases synaptic integrity that leads to long-term loss of sensorimotor, behavioral, and cognitive functions.

The rationale of the proposed research is to understand the mechanisms that underlie the cumulative and synergistic effects of radiation exposure, isolation confinement stress, and altered gravity on behavioral, cognitive, and sensorimotor deficits. Further, we will explore sex-dimorphic responses along with potential peripheral biomarkers associated with simulated deep space travel. Our studies will provide novel information regarding the cellular mechanisms of altered neuronal function involved in simulated deep space conditions (GCRsim, isolation confinement, and altered gravity). Finally, we will incorporate all the results to build risk assessment and performance decrement for astronauts.

We will characterize molecular, cellular, tissue, and behavioral endpoints underlying CNS function in an individual manner with animals prescreening. We will use multiple behavioral and cognitive tests known to be comparable to human performance. We will use state of the art techniques to dissect cellular and molecular changes in the brain. The endpoints will be selected to probe key physiological processes that support tissue homeostasis plasticity in the brain. We will determine if and how cellular and molecular impairments are linked to compromised behavior in motor, social, and cognitive domains. By combining assessments of multiple processes that may have distinct time constants and magnitudes of responses to simulated deep space conditions we will begin to identify operationally-relevant brain functions impacted by the three stressors and relate these to human performance. Furthermore, by comparing outcome measures in both males and females we will begin to understand the distinct aspects of the responses controlled by sex and are therefore more likely to translate to humans.

The proposed aims directly address Human Exploration Research Opportunities (HERO) announcement needs detailed in Appendix A that specify research needs (gaps) related to NASA Research and Technology Development to Support Crew Health and Performance in Space Exploration Missions. The specific gaps this proposal addresses are Topic 1, gap CNS 1 (Are there significant adverse changes in CNS performance in the context and time scale of spaceflight operations? If so, how is significance defined, and which neuropsychological domains are affected? Is there a significant probability that space radiation exposure would result in adverse changes? What are the pathways and mechanisms of change?), CNS 2 (Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers (in-flight or post-flight)?), CNS 5 (How can new knowledge and data from molecular, cellular, tissue and animal models of acute CNS adverse changes or clinical human data, including altered motor and cognitive function and behavioral changes be used to estimate acute CNS risks to astronauts from GCR and SPE-solar particle event?), SM6.1 (Determine if sensorimotor dysfunction during and after long-duration spaceflight affects ability to control spacecraft and associated systems), SM 26 (Determine if exposure to long-duration spaceflight leads to neural structural alterations and if this remodeling impacts cognitive and functional performance), and IM 8 (IM8: We do not know the influence, direct, or synergistic, on the immune system of other physiological changes associated with spaceflight). [Ed. note November 2021: Gaps have been revised since the original proposal Task Description; please refer to the Human Research Roadmap for current gap information: https://humanresearchroadmap.nasa.gov/ ]

The central hypothesis of this proposal is that there is a synergistic effect of multiple factors (defined by GCRsim, isolation confinement stress, and altered gravity) encountered in deep space exposure that leads to enhanced inflammatory response, promotes synapse loss, and decreases synaptic integrity that leads to long-term loss of sensorimotor, behavioral, and cognitive functions.

The rationale of the proposed research is to understand the mechanisms that underlie the cumulative and synergistic effects of radiation exposure, isolation confinement stress, and altered gravity on behavioral, cognitive, and sensorimotor deficits. Further, we will explore sex-dimorphic responses along with potential peripheral biomarkers associated with simulated deep space travel. Our studies will provide novel information regarding the cellular mechanisms of altered neuronal function involved in simulated deep space conditions (GCRsim, isolation confinement, and altered gravity). Finally, we will incorporate all the results to build risk assessment and performance decrement for astronauts.

We will characterize molecular, cellular, tissue, and behavioral endpoints underlying CNS function in an individual manner with animals prescreening. We will use multiple behavioral and cognitive tests known to be comparable to human performance. We will use state of the art techniques to dissect cellular and molecular changes in the brain. The endpoints will be selected to probe key physiological processes that support tissue homeostasis plasticity in the brain. We will determine if and how cellular and molecular impairments are linked to compromised behavior in motor, social, and cognitive domains. By combining assessments of multiple processes that may have distinct time constants and magnitudes of responses to simulated deep space conditions we will begin to identify operationally-relevant brain functions impacted by the three stressors and relate these to human performance. Furthermore, by comparing outcome measures in both males and females we will begin to understand the distinct aspects of the responses controlled by sex and are therefore more likely to translate to humans.

The proposed aims directly address Human Exploration Research Opportunities (HERO) announcement needs detailed in Appendix A that specify research needs (gaps) related to NASA Research and Technology Development to Support Crew Health and Performance in Space Exploration Missions. The specific gaps this proposal addresses are Topic 1, gap CNS 1 (Are there significant adverse changes in CNS performance in the context and time scale of spaceflight operations? If so, how is significance defined, and which neuropsychological domains are affected? Is there a significant probability that space radiation exposure would result in adverse changes? What are the pathways and mechanisms of change?), CNS 2 (Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers (in-flight or post-flight)?), CNS 5 (How can new knowledge and data from molecular, cellular, tissue and animal models of acute CNS adverse changes or clinical human data, including altered motor and cognitive function and behavioral changes be used to estimate acute CNS risks to astronauts from GCR and SPE-solar particle event?), SM6.1 (Determine if sensorimotor dysfunction during and after long-duration spaceflight affects ability to control spacecraft and associated systems), SM 26 (Determine if exposure to long-duration spaceflight leads to neural structural alterations and if this remodeling impacts cognitive and functional performance), and IM 8 (IM8: We do not know the influence, direct, or synergistic, on the immune system of other physiological changes associated with spaceflight). [Ed. note November 2021: Gaps have been revised since the original proposal Task Description; please refer to the Human Research Roadmap for current gap information: https://humanresearchroadmap.nasa.gov/ ]

The central hypothesis of this proposal is that there is a synergistic effect of multiple factors (defined by GCRsim, isolation confinement stress, and altered gravity) encountered in deep space exposure that leads to enhanced inflammatory response, promotes synapse loss, and decreases synaptic integrity that leads to long-term loss of sensorimotor, behavioral, and cognitive functions.

The rationale of the proposed research is to understand the mechanisms that underlie the cumulative and synergistic effects of radiation exposure, isolation confinement stress, and altered gravity on behavioral, cognitive, and sensorimotor deficits. Further, we will explore sex-dimorphic responses along with potential peripheral biomarkers associated with simulated deep space travel. Our studies will provide novel information regarding the cellular mechanisms of altered neuronal function involved in simulated deep space conditions (GCRsim, isolation confinement, and altered gravity). Finally, we will incorporate all the results to build risk assessment and performance decrement for astronauts.

We will characterize molecular, cellular, tissue, and behavioral endpoints underlying CNS function in an individual manner with animals prescreening. We will use multiple behavioral and cognitive tests known to be comparable to human performance. We will use state of the art techniques to dissect cellular and molecular changes in the brain. The endpoints will be selected to probe key physiological processes that support tissue homeostasis plasticity in the brain. We will determine if and how cellular and molecular impairments are linked to compromised behavior in motor, social, and cognitive domains. By combining assessments of multiple processes that may have distinct time constants and magnitudes of responses to simulated deep space conditions we will begin to identify operationally-relevant brain functions impacted by the three stressors and relate these to human performance. Furthermore, by comparing outcome measures in both males and females we will begin to understand the distinct aspects of the responses controlled by sex and are therefore more likely to translate to humans.

The proposed aims directly address Human Exploration Research Opportunities (HERO) announcement needs detailed in Appendix A that specify research needs (gaps) related to NASA Research and Technology Development to Support Crew Health and Performance in Space Exploration Missions. The specific gaps this proposal addresses are Topic 1, gap CNS 1 (Are there significant adverse changes in CNS performance in the context and time scale of spaceflight operations? If so, how is significance defined, and which neuropsychological domains are affected? Is there a significant probability that space radiation exposure would result in adverse changes? What are the pathways and mechanisms of change?), CNS 2 (Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers (in-flight or post-flight)?), CNS 5 (How can new knowledge and data from molecular, cellular, tissue and animal models of acute CNS adverse changes or clinical human data, including altered motor and cognitive function and behavioral changes be used to estimate acute CNS risks to astronauts from GCR and SPE-solar particle event?), SM6.1 (Determine if sensorimotor dysfunction during and after long-duration spaceflight affects ability to control spacecraft and associated systems), SM 26 (Determine if exposure to long-duration spaceflight leads to neural structural alterations and if this remodeling impacts cognitive and functional performance), and IM 8 (IM8: We do not know the influence, direct, or synergistic, on the immune system of other physiological changes associated with spaceflight).

Assurance of high quality, integrated-risk research

Standardization of approaches/rationale

Mechanisms to maintain communications (and reduce site burdens)

Consistent information

Efficiently/effectively integrate research efforts

Data management

Integration of research data

Research data submission formats

Computational modeling lead

Throughout the definition phase the Ronca, Rosi, and Sanford groups have agreed upon the A) standardizations (where possible without changing the study objectives) of experimental design for exposure regimen, husbandry, animal sex and ages and data collection schedules. In addition to the animal care specifics, we have developed a unified model for combined space stress that will be used at Brookhaven National Laboratory (BNL) by all investigators, stages of which will be followed by each grant’s specific aims. In brief, all animals will have an identical length of time at BNL under the same husbandry conditions including same diet, undergo the same acclimation, social isolation, microgravity model, GCR dose, similar euthanasia methods, and a minimum of one unified downstream marker in both the blood and brain. To maintain standardization across the three VNSCOR investigators have agreed on: time at BNL, dose, diet, parasite protection, cognitive measures, and blood biomarkers.

Due to COVID-19 we were not able to proceed with Aim 1 as planned. These experiments have been postponed to Spring 2021.

The central hypothesis of this proposal is that there is a synergistic effect of multiple factors (defined by GCRsim, isolation confinement stress, and altered gravity) encountered in deep space exposure that leads to enhanced inflammatory response, promotes synapse loss, and decreases synaptic integrity that leads to long-term loss of sensorimotor, behavioral, and cognitive functions.

The rationale of the proposed research is to understand the mechanisms that underlie the cumulative and synergistic effects of radiation exposure, isolation confinement stress, and altered gravity on behavioral, cognitive, and sensorimotor deficits. Further, we will explore sex-dimorphic responses along with potential peripheral biomarkers associated with simulated deep space travel. Our studies will provide novel information regarding the cellular mechanisms of altered neuronal function involved in simulated deep space conditions (GCRsim, isolation confinement, and altered gravity). Finally, we will incorporate all the results to build risk assessment and performance decrement for astronauts.

We will characterize molecular, cellular, tissue, and behavioral endpoints underlying CNS function in an individual manner with animals prescreening. We will use multiple behavioral and cognitive tests known to be comparable to human performance. We will use state of the art techniques to dissect cellular and molecular changes in the brain. The endpoints will be selected to probe key physiological processes that support tissue homeostasis plasticity in the brain. We will determine if and how cellular and molecular impairments are linked to compromised behavior in motor, social, and cognitive domains. By combining assessments of multiple processes that may have distinct time constants and magnitudes of responses to simulated deep space conditions we will begin to identify operationally-relevant brain functions impacted by the three stressors and relate these to human performance. Furthermore, by comparing outcome measures in both males and females we will begin to understand the distinct aspects of the responses controlled by sex and are therefore more likely to translate to humans.

The proposed aims directly address Human Exploration Research Opportunities (HERO) announcement needs detailed in Appendix A that specify research needs (gaps) related to NASA Research and Technology Development to Support Crew Health and Performance in Space Exploration Missions. The specific gaps this proposal addresses are Topic 1, gap CNS 1 (Are there significant adverse changes in CNS performance in the context and time scale of spaceflight operations? If so, how is significance defined, and which neuropsychological domains are affected? Is there a significant probability that space radiation exposure would result in adverse changes? What are the pathways and mechanisms of change?), CNS 2 (Does space radiation exposure elicit key events in adverse outcome pathways associated with neurological diseases? What are the key events or hallmarks, their time sequence and their associated biomarkers (in-flight or post-flight)?), CNS 5 (How can new knowledge and data from molecular, cellular, tissue and animal models of acute CNS adverse changes or clinical human data, including altered motor and cognitive function and behavioral changes be used to estimate acute CNS risks to astronauts from GCR and SPE?), SM6.1 (Determine if sensorimotor dysfunction during and after long-duration spaceflight affects ability to control spacecraft and associated systems), SM 26 (Determine if exposure to long-duration spaceflight leads to neural structural alterations and if this remodeling impacts cognitive and functional performance), and IM 8 (IM8: We do not know the influence, direct, or synergistic, on the immune system of other physiological changes associated with spaceflight).