Apolipoprotein E4 Mediates Insulin Resistance-Associated Cerebrovascular Dysfunction and the Post-Prandial Response

Metabolic dysfunction, commonly a result of diets high in saturated fats and sugar, is associated with impaired cognitive function and an increased risk of age-related cognitive decline (ACD) and Alzheimer’s disease (AD). Compared to the E3 isoform of apolipoprotein (apoE), the E4 isoform is a major genetic risk factor for ACD, AD, and for developing cognitive impairments following various environmental challenges, including dietary challenges such as a high-fat diet (HFD). Both insulin resistance (IR) and E4 are associated with metabolic and vascular impairments. Deficits in cerebral metabolism and cerebrovascular function have been proposed as initiating events leading to these impairments. In the current study, we employed a model of human apoE targeted replacement mice and HFD-induced obesity to study the potential link between E4 and IR, at rest and following a postprandial challenge. HFD-induced IR was associated with impaired cognition, reduced cerebral blood volume and decreased glucose uptake. These effects were more profound in E4 than E3 mice. Furthermore, the cognitive, metabolic and cerebrovascular responses to an exogenous glucose load showed an apoE isoform-dependent response, with E4, but not E3 mice, acutely benefiting from a spike in blood glucose

Modeling the cognitive effects of diet discontinuation in adults with phenylketonuria (PKU) using pegvaliase therapy in PAH-deficient mice

Existing phenylalanine hydroxylase (PAH)-deficient mice strains are useful models of untreated or late-treated human phenylketonuria (PKU), as most contemporary therapies can only be initiated after weaning and the pups have already suffered irreversible consequences of chronic hyperphenylalaninemia (HPA) during early brain development. Therefore, we sought to evaluate whether enzyme substitution therapy with pegvaliase initiated near birth and administered repetitively to C57Bl/6-Pahenu2/enu2 mice would prevent HPA-related behavioral and cognitive deficits and form a model for early-treated PKU. The main results of three reported experiments are: 1) lifelong weekly pegvaliase treatment prevented the cognitive deficits associated with HPA in contrast to persisting deficits in mice treated with pegvaliase only as adults. 2) Cognitive deficits reappear in mice treated with weekly pegvaliase from birth but in which pegvaliase is discontinued at 3 months age. 3) Twice weekly pegvaliase injection also prevented cognitive deficits but again cognitive deficits emerged in early-treated animals following discontinuation of pegvaliase treatment during adulthood, particularly in females. In all studies, pegvaliase treatment was associated with complete correction of brain monoamine neurotransmitter content and with improved overall growth of the mice as measured by body weight. Mean total brain weight however remained low in all PAH deficient mice regardless of treatment. Application of enzyme substitution therapy with pegvaliase, initiated near birth and continued into adulthood, to PAH-deficient Pahenu2/enu2 mice models contemporary early-treated human PKU. This model will be useful for exploring the differential pathophysiologic effects of HPA at different developmental stages of the murine brain. Keywords: Behavior; Cognition; Dopamine; Hyperphenylalaninemia; Pegvaliase; Phenylalanine hydroxylase; Phenylketonuria; Serotonin; Tryptophan; Tryptophan hydroxylase; Tyrosine; Tyrosine hydroxylase

The neuroscience of social feelings:mechanisms of adaptive social functioning

Social feelings have conceptual and empirical connections with affect and emotion. In this review, we discuss how they relate to cognition, emotion, behavior and well-being. We examine the functional neuroanatomy and neurobiology of social feelings and their role in adaptive social functioning. Existing neuroscience literature is reviewed to identify concepts, methods and challenges that might be addressed by social feelings research. Specific topic areas highlight the influence and modulation of social feelings on interpersonal affiliation, parent-child attachments, moral sentiments, interpersonal stressors, and emotional communication. Brain regions involved in social feelings were confirmed by meta-analysis using the Neurosynth platform for large-scale, automated synthesis of functional magnetic resonance imaging data. Words that relate specifically to social feelings were identfied as potential research variables. Topical inquiries into social media behaviors, loneliness, trauma, and social sensitivity, especially with recent physical distancing for guarding public and personal health, underscored the increasing importance of social feelings for affective and second person neuroscience research with implications for brain development, physical and mental health, and lifelong adaptive functioning

Anticipatory feelings: Neural correlates and linguistic markers

This review introduces anticipatory feelings (AF) as a new construct related to the process of anticipation and prediction of future events. AF, defined as the state of awareness of physiological and neurocognitive changes that occur within an oganism in the form of a process of adapting to future events, are an important component of anticipation and expectancy. They encompass bodily-related interoceptive and affective components and are influenced by intrapersonal and dispositional factors, such as optimism, hope, pessimism, or worry. In the present review, we consider evidence from animal and human research, including neuroimaging studies, to characterize the brain structures and brain networks involved in AF. The majority of studies reviewed revealed three brain regions involved in future oriented feelings: 1) the insula; 2) the ventromedial prefrontal cortex (vmPFC); and 3) the amygdala. Moreover, these brain regions were confirmed by a meta-analysis, using a platform for large-scale, automated synthesis of fMRI data. Finally, by adopting a neurolinguistic and a big data approach, we illustrate how AF are expressed in language

Space Radiation Alters Genotype–Phenotype Correlations in Fear Learning and Memory Tests

Behavioral and cognitive traits have a genetic component even though contributions from individual genes and genomic loci are in many cases modest. Changes in the environment can alter genotype–phenotype relationships. Space travel, which includes exposure to ionizing radiation, constitutes environmental challenges and is expected to induce not only dramatic behavioral and cognitive changes but also has the potential to induce physical DNA damage. In this study, we utilized a genetically heterogeneous mouse model, dense genotype data, and shifting environmental challenges, including ionizing radiation exposure, to explore and quantify the size and stability of the genetic component of fear learning and memory-related measures. Exposure to ionizing radiation and other external stressors altered the genotype–phenotype correlations, although different behavioral and cognitive measures were affected to different extents. Utilizing an integrative genomic approach, we identified pathways and functional ontology categories associated with these behavioral and cognitive measures

An Adaptive Role for DNA Double-Strand Breaks in Hippocampus-Dependent Learning and Memory

DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients diagnosed with mild cognitive impairment (MCI) or Alzheimer’s disease (AD) show increased DSBs. A novel role for DSBs in immediate early gene (IEG) expression, learning, and memory has been suggested. Inducing neuronal activity leads to increases in DSBs and upregulation of IEGs, while increasing DSBs and inhibiting DSB repair impairs long-term memory and alters IEG expression. Consistent with this pattern, mice carrying dominant AD mutations have increased baseline DSBs, and impaired DSB repair is observed. These data suggest an adaptive role for DSBs in the central nervous system and dysregulation of DSBs and/or repair might drive age-related cognitive decline (ACD), MCI, and AD. In this review, we discuss the adaptive role of DSBs in hippocampus-dependent learning, memory, and IEG expression. We summarize IEGs, the history of DSBs, and DSBs in synaptic plasticity, aging, and AD. DSBs likely have adaptive functions in the brain, and even subtle alterations in their formation and repair could alter IEGs, learning, and memory

Detrimental Effects of Helium Ion Irradiation on Cognitive Performance and Cortical Levels of MAP-2 in B6D2F1 Mice.

The space radiation environment includes helium (⁴He) ions that may impact brain function. As little is known about the effects of exposures to ⁴He ions on the brain, we assessed the behavioral and cognitive performance of C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation with ⁴He ions (250 MeV/n; linear energy transfer (LET) = 1.6 keV/μm; 0, 21, 42 or 168 cGy). Sham-irradiated mice and mice irradiated with 21 or 168 cGy showed novel object recognition, but mice irradiated with 42 cGy did not. In the passive avoidance test, mice received a slight foot shock in a dark compartment, and latency to re-enter that compartment was assessed 24 h later. Sham-irradiated mice and mice irradiated with 21 or 42 cGy showed a higher latency on Day 2 than Day 1, but the latency to enter the dark compartment in mice irradiated with 168 cGy was comparable on both days. ⁴He ion irradiation, at 42 and 168 cGy, reduced the levels of the dendritic marker microtubule-associated protein-2 (MAP-2) in the cortex. There was an effect of radiation on apolipoprotein E (apoE) levels in the hippocampus and cortex, with higher apoE levels in mice irradiated at 42 cGy than 168 cGy and a trend towards higher apoE levels in mice irradiated at 21 than 168 cGy. In addition, in the hippocampus, there was a trend towards a negative correlation between MAP-2 and apoE levels. While reduced levels of MAP-2 in the cortex might have contributed to the altered performance in the passive avoidance test, it does not seem sufficient to do so. The higher hippocampal and cortical apoE levels in mice irradiated at 42 than 168 cGy might have served as a compensatory protective response preserving their passive avoidance memory. Thus, there were no alterations in behavioral performance in the open filed or depressive-like behavior in the forced swim test, while cognitive impairments were seen in the object recognition and passive avoidance tests, but not in the contextual or cued fear conditioning tests. Taken together, the results indicate that some aspects of cognitive performance are altered in male mice exposed to ⁴He ions, but that the response is task-dependent. Furthermore, the sensitive doses can vary within each task in a non-linear fashion. This highlights the importance of assessing the cognitive and behavioral effects of charged particle exposure with a variety of assays and at multiple doses, given the possibility that lower doses may be more damaging due to the absence of induced compensatory mechanisms at higher doses

Detrimental Effects of Helium Ion Irradiation on Cognitive Performance and Cortical Levels of MAP-2 in B6D2F1 Mice

The space radiation environment includes helium (4He) ions that may impact brain function. As little is known about the effects of exposures to 4He ions on the brain, we assessed the behavioral and cognitive performance of C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation with 4He ions (250 MeV/n; linear energy transfer (LET) = 1.6 keV/μm; 0, 21, 42 or 168 cGy). Sham-irradiated mice and mice irradiated with 21 or 168 cGy showed novel object recognition, but mice irradiated with 42 cGy did not. In the passive avoidance test, mice received a slight foot shock in a dark compartment, and latency to re-enter that compartment was assessed 24 h later. Sham-irradiated mice and mice irradiated with 21 or 42 cGy showed a higher latency on Day 2 than Day 1, but the latency to enter the dark compartment in mice irradiated with 168 cGy was comparable on both days. 4He ion irradiation, at 42 and 168 cGy, reduced the levels of the dendritic marker microtubule-associated protein-2 (MAP-2) in the cortex. There was an effect of radiation on apolipoprotein E (apoE) levels in the hippocampus and cortex, with higher apoE levels in mice irradiated at 42 cGy than 168 cGy and a trend towards higher apoE levels in mice irradiated at 21 than 168 cGy. In addition, in the hippocampus, there was a trend towards a negative correlation between MAP-2 and apoE levels. While reduced levels of MAP-2 in the cortex might have contributed to the altered performance in the passive avoidance test, it does not seem sufficient to do so. The higher hippocampal and cortical apoE levels in mice irradiated at 42 than 168 cGy might have served as a compensatory protective response preserving their passive avoidance memory. Thus, there were no alterations in behavioral performance in the open filed or depressive-like behavior in the forced swim test, while cognitive impairments were seen in the object recognition and passive avoidance tests, but not in the contextual or cued fear conditioning tests. Taken together, the results indicate that some aspects of cognitive performance are altered in male mice exposed to 4He ions, but that the response is task-dependent. Furthermore, the sensitive doses can vary within each task in a non-linear fashion. This highlights the importance of assessing the cognitive and behavioral effects of charged particle exposure with a variety of assays and at multiple doses, given the possibility that lower doses may be more damaging due to the absence of induced compensatory mechanisms at higher doses

Effects of Six Sequential Charged Particle Beams on Behavioral and Cognitive Performance in B6D2F1 Female and Male Mice.

The radiation environment astronauts are exposed to in deep space includes galactic cosmic radiation (GCR) with different proportions of all naturally occurring ions. To assist NASA with assessment of risk to the brain following exposure to a mixture of ions broadly representative of the GCR, we assessed the behavioral and cognitive performance of female and male C57BL/6J × DBA2/J F1 (B6D2F1) mice two months following rapidly delivered, sequential 6 beam irradiation with protons (1 GeV, LET = 0.24 keV, 50%), 4He ions (250 MeV/n, LET = 1.6 keV/μm, 20%), 16O ions (250 MeV/n, LET = 25 keV/μm 7.5%), 28Si ions (263 MeV/n, LET = 78 keV/μm, 7.5%), 48Ti ions (1 GeV/n, LET = 107 keV/μm, 7.5%), and 56Fe ions (1 GeV/n, LET = 151 keV/μm, 7.5%) at 0, 25, 50, or 200 cGy) at 4-6 months of age. When the activity over 3 days of open field habituation was analyzed in female mice, those irradiated with 50 cGy moved less and spent less time in the center than sham-irradiated mice. Sham-irradiated female mice and those irradiated with 25 cGy showed object recognition. However, female mice exposed to 50 or 200 cGy did not show object recognition. When fear memory was assessed in passive avoidance tests, sham-irradiated mice and mice irradiated with 25 cGy showed memory retention while mice exposed to 50 or 200 cGy did not. The effects of radiation passive avoidance memory retention were not sex-dependent. There was no effect of radiation on depressive-like behavior in the forced swim test. There was a trend toward an effect of radiation on BDNF levels in the cortex of males, but not for females, with higher levels in male mice irradiated with 50 cGy than sham-irradiated. Finally, sequential 6-ion irradiation impacted the composition of the gut microbiome in a sex-dependent fashion. Taxa were uncovered whose relative abundance in the gut was associated with the radiation dose received. Thus, exposure to sequential six-beam irradiation significantly affects behavioral and cognitive performance and the gut microbiome