Psychological Resilience to the Challenges of Physical Aging in Older U.S. Veterans: Results From the 2019-2020 National Health and Resilience in Veterans Study.

OBJECTIVES: To employ a novel analytic approach to quantify psychological resilience to physical health difficulties and identify factors associated with greater resilience in older U.S. veterans. METHODS: Data from a nationally representative sample of older U.S. military veterans (N = 3,001), who participated in the National Health and Resilience in Veterans Study were analyzed to develop the Psychological Resilience Against Physical Difficulties Index (PRAPDI). Multiple regression and relative importance analyses were conducted to identify factors associated with greater PRAPDI scores. RESULTS: Secure attachment style [17.3% relative variance explained (RVE)], mindfulness [16.6% RVE], and purpose in life [15.0% RVE] emerged as the strongest correlates of PRAPDI scores. CONCLUSION: Intervention strategies aimed at fostering mindfulness, attachment security, and purpose in life may help promote psychological resilience to the challenges of physical aging in older veterans.

Perinatal dietary omega-3 fatty acid deficiency reduces maternal nurturing behavior in rats: dissociation from elevated pro-inflammatory signaling.

Objectives: Maternal-pup nurturing behavior has previously been shown to impact offspring neurodevelopment independent of diet. Here we investigated the effects of perinatal maternal n-3 fatty acid deficiency on maternal-pup nurturing behavior and potential associations with pro-inflammatory signaling.Methods: Eight-week-old virgin female Long-Evans hooded rats were randomized to a control diet containing alpha-linolenic acid (ALA, 18:3n-3) (CON, n = 10) or an ALA-free diet (Deficient, DEF, n = 11) 30 d prior to mating. On postnatal day 2 (P2) litters were culled to eight per dam. On P3, P6, and P9 dams and their litters were video recorded and maternal nurturing behaviors, including licking/grooming of pups and arched-back nursing, were scored by a blinded rater. Following weaning on P21, dam postmortem central (prefrontal cortex, PFC) and peripheral (red blood cell, RBC) fatty acid composition and central (PFC IL-1ß, IL-2, IL-6, TNFα, cPLA2, COX-2 mRNA) and peripheral (plasma IL-1ß, IL-2, IL-6, TNFα, CRP) pro-inflammatory biostatus assessed.Results: DEF dams exhibited significantly lower RBC (p ≤ 0.0001) and PFC (p ≤ 0.0001) docosahexaenoic acid (DHA) levels compared with CON dams. Irrespective of diet dams exhibited significantly lower RBC, but not PFC, DHA levels compared with non-parous rats. DEF dams exhibited less licking/grooming (p = 0.008), arched-back nursing (p ≤ 0.0001) and blanket nursing (p = 0.003), and exhibited more passive nursing (p = 0.003) but not time off pups (p = 0.1), compared with CON dams. PFC and plasma inflammatory measures did not differ significantly between groups.Discussion: Perinatal dietary n-3 fatty acid deficiency reduces maternal nurturing behavior and this effect is not associated with enduring elevations in pro-inflammatory signaling.

Omega-3 fatty acid deficiency impairs frontostriatal recruitment following repeated amphetamine treatment in rats: A 7 Tesla in vivo phMRI study.

Although attention deficit hyperactivity disorder is associated with deficits in docosahexaenoic acid (DHA), an omega-3 fatty acid implicated in dopamine and glutamate synaptic plasticity, its role in neuroplastic brain changes that occur following repeated amphetamine (AMPH) treatment are not known. This study used pharmacological magnetic resonance imaging to investigate the impact of repeated AMPH exposure and alterations in brain DHA levels on AMPH-induced brain activation patterns. Male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (n = 20) from P21 to P90. During adolescence (P40-60), one-half of each diet group received daily AMPH injections escalated weekly (0.5, 1.0, 2.5, 5.0 mg/kg/d) or drug vehicle. Following a 30-d abstinence period blood oxygen level dependent (BOLD) responses were determined in a 7 T Bruker Biospec system following an AMPH challenge (7.5 mg/kg, i.v). Postmortem erythrocyte and forebrain DHA composition were determined by gas chromatography. Compared with control rats, forebrain and erythrocyte DHA levels were significantly lower in DEF rats and significantly higher in FO rats. Across AMPH doses DEF rats exhibited greater locomotor activity compared to control and FO rats. In AMPH-naïve rats, the AMPH challenge increased BOLD activity in the substantia nigra and basal forebrain and no diet group differences were observed. In AMPH-pretreated control and FO rats, the AMPH challenge similarly increased BOLD activation in the bilateral caudate putamen, thalamus, and motor and cingulate cortices. In contrast, BOLD activation in AMPH-pretreated DEF rats was similar to AMPH-naïve DEF animals, and AMPH-pretreated DEF rats exhibited attenuated frontostriatal BOLD activation compared with AMPH-pretreated control and FO rats. These findings demonstrate that chronic escalating AMPH treatment induces enduring frontostriatal recruitment and that peri-adolescent deficits in brain DHA accrual impair this response.

Deficits in Docosahexaenoic Acid Accrual during Adolescence Reduce Rat Forebrain White Matter Microstructural Integrity: An in vivo Diffusion Tensor Imaging Study.

Neuropsychiatric disorders that frequently initially emerge during adolescence are associated with deficits in the omega-3 (n-3) fatty acid docosahexaenoic acid (DHA), elevated proinflammatory signaling, and regional reductions in white matter integrity (WMI). This study determined the effects of altering brain DHA accrual during adolescence on WMI in the rat brain by diffusion tensor imaging (DTI), and investigated the potential mediating role of proinflammatory signaling. During periadolescent development, male rats were fed a diet deficient in n-3 fatty acids (DEF, n = 20), a fish oil-fortified diet containing preformed DHA (FO, n = 20), or a control diet (CON, n = 20). In adulthood, DTI scans were performed and brain WMI was determined using voxelwise tract-based spatial statistics (TBSS). Postmortem fatty acid composition, peripheral (plasma IL-1ß, IL-6, and C-reactive protein [CRP]) and central (IL-1ß and CD11b mRNA) proinflammatory markers, and myelin basic protein (MBP) mRNA expression were determined. Compared with CON rats, forebrain DHA levels were lower in DEF rats and higher in FO rats. Compared with CON rats, DEF rats exhibited greater radial diffusivity (RD) and mean diffusivity in the right external capsule, and greater axial diffusivity in the corpus callosum genu and left external capsule. DEF rats also exhibited greater RD than FO rats in the right external capsule. Forebrain MBP expression did not differ between groups. Compared with CON rats, central (IL-1ß and CD11b) and peripheral (IL-1ß and IL-6) proinflammatory markers were not different in DEF rats, and DEF rats exhibited lower CRP levels. These findings demonstrate that deficits in adolescent DHA accrual negatively impact forebrain WMI, independently of elevated proinflammatory signaling.

Preliminary Study of White Matter Abnormalities and Associations With the Metabotropic Glutamate Receptor 5 to Distinguish Bipolar and Major Depressive Disorders.

Background: Understanding distinct neurobiological mechanisms underlying bipolar disorder (BD) and major depressive disorder (MDD) is crucial for accurate diagnosis and the discovery of novel and more effective targeted treatments. Previous diffusion-weighted MRI studies have suggested some common frontotemporal corticolimbic system white matter (WM) abnormalities across the disorders. However, critical to the development of more precise diagnosis and treatment is identifying distinguishing abnormalities. Promising candidates include more prominent frontotemporal WM abnormalities observed in BD in the uncinate fasciculus (UF) that have been associated with frontal-amygdala functional dysconnectivity, and with suicide that is especially high in BD. Prior work also showed differentiation in metabotropic glutamate receptor 5 (mGlu5) abnormalities in BD versus MDD, which could be a mechanism affected in the frontotemporal system. However, associations between WM and mGlu5 have not been examined previously as a differentiator of BD. Using a multimodal neuroimaging approach, we examined WM integrity alterations in the disorders and their associations with mGluR5 levels. Methods: Individuals with BD (N = 21), MDD (N = 10), and HC (N = 25) participated in structural and diffusion-weighted MRI scanning, and imaging with [18F]FPEB PET for quantification of mGlu5 availability. Whole-brain analyses were used to assess corticolimbic WM matter fractional anisotropy (FA) across BD and MDD relative to HC; abnormalities were tested for associations with mGlu5 availability. Results: FA corticolimbic reductions were observed in both disorders and altered UF WM integrity was observed only in BD. In BD, lower UF FA was associated with lower amygdala mGlu5 availability (p < .05). Conclusions: These novel preliminary findings suggest important associations between lower UF FA and lower amygdala mGlu5 levels that could represent a disorder-specific neural mechanism in which mGluR5 is associated with the frontotemporal dysconnectivity of the disorder.

Deficits in prefrontal metabotropic glutamate receptor 5 are associated with functional alterations during emotional processing in bipolar disorder.

BACKGROUND: Elucidating biological mechanisms contributing to bipolar disorder (BD) is key to improved diagnosis and treatment development. With converging evidence implicating the metabotropic glutamate receptor 5 (mGlu5) in the pathology of BD, here, we therefore test the hypothesis that recently identified deficits in mGlu5 are associated with functional brain differences during emotion processing in BD. METHODS: Positron emission tomography (PET) with [18F]FPEB was used to measure mGlu5 receptor availability and functional imaging (fMRI) was performed while participants completed an emotion processing task. Data were analyzed from 62 individuals (33 ± 12 years, 45 % female) who completed both PET and fMRI, including individuals with BD (n = 18), major depressive disorder (MDD: n = 20), and psychiatrically healthy comparisons (HC: n = 25). RESULTS: Consistent with some prior reports, the BD group displayed greater activation during fear processing relative to MDD and HC, notably in right lateralized frontal and parietal brain regions. In BD, (but not MDD or HC) lower prefrontal mGlu5 availability was associated with greater activation in bilateral pre/postcentral gyri and cuneus during fear processing. Furthermore, greater prefrontal mGlu5-related brain activity in BD was associated with difficulties in psychomotor function (r≥0.904, p≤0.005) and attention (r≥0.809, p≤0.028). LIMITATIONS: The modest sample size is the primary limitation. CONCLUSIONS: Deficits in prefrontal mGlu5 in BD were linked to increased cortical activation during fear processing, which in turn was associated with impulsivity and attentional difficulties. These data further implicate an mGlu5-related mechanism unique to BD. More generally these data suggest integrating PET and fMRI can provide novel mechanistic insights.

The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders.

The role of glutamate system in the etiology and pathophysiology of psychiatric disorders has gained considerable attention in the past two decades, including dysregulation of the metabotropic glutamatergic receptor subtype 5 (mGlu5). Thus, mGlu5 may represent a promising therapeutic target for psychiatric conditions, particularly stress-related disorders. Here, we describe mGlu5 findings in mood disorders, anxiety, and trauma disorders, as well as substance use (specifically nicotine, cannabis, and alcohol use). We highlight insights gained from positron emission tomography (PET) studies, where possible, and discuss findings from treatment trials, when available, to explore the role of mGlu5 in these psychiatric disorders. Through the research evidence reviewed in this chapter, we make the argument that, not only is dysregulation of mGlu5 evident in numerous psychiatric disorders, potentially functioning as a disease "biomarker," the normalization of glutamate neurotransmission via changes in mGlu5 expression and/or modulation of mGlu5 signaling may be a needed component in treating some psychiatric disorders or symptoms. Finally, we hope to demonstrate the utility of PET as an important tool for investigating mGlu5 in disease mechanisms and treatment response.

Evaluating infusion methods and simplified quantification of synaptic density in vivo with [11C]UCB-J and [18F]SynVesT-1 PET.

For some positron emission tomography studies, radiotracer is administered as bolus plus continuous infusion (B/I) to achieve a state of equilibrium. This approach can reduce scanning time and simplify data analysis; however, the method must be validated and optimized for each tracer. This study aimed to validate a B/I method for in vivo quantification of synaptic density using radiotracers which target the synaptic vesicle glycoprotein 2 A: [11C]UCB-J and [18F]SynVesT-1. Observed mean standardized uptake values (SUV) in target tissue relative to that in plasma (CT/CP) or a reference tissue (SUVR-1) were calculated for 30-minute intervals across 120 or 150-minute dynamic scans and compared against one-tissue compartment (1TC) model estimates of volume of distribution (VT) and binding potential (BPND), respectively. We were unable to reliably achieve a state of equilibrium with [11C]UCB-J, and all 30-minute windows yielded overly large bias and/or variability for CT/CP and SUVR-1. With [18F]SynVesT-1, a 30-minute scan 90-120 minutes post-injection yielded CT/CP and SUVR-1 values that estimated their respective kinetic parameter with sufficient accuracy and precision (within 7±6%) . This B/I approach allows a clinically feasible scan at equilibrium with potentially better accuracy than a static scan SUVR following a bolus injection.

Examining mGlu5 Receptor Availability as a Predictor of Vulnerability to PTSD: An [18F]FPEB and PET Study in Male and Female Rats.

Background: Females are twice as likely to experience post-traumatic stress disorder (PTSD) than males, yet specific factors contributing to this greater risk are not fully understood. Our clinical and recent preclinical findings suggest a role for the metabotropic glutamate receptor 5 (mGlu5) in PTSD and differential involvement between males and females. Methods: Here, we further investigate whether mGlu5 receptor availability may contribute to individual and sex differences in PTSD susceptibility by quantifying receptor availability using the mGlu5 receptor-specific radiotracer, [18F]FPEB, and positron emission tomography in male (n = 16) and female (n = 16) rats before and after traumatic footshock exposure (FE) and assessment of stress-enhanced fear learning (SEFL) susceptibility, as compared with no-shock controls (CON; n = 7 male; n = 8 female). Results: Overall, FE rats displayed greater fear generalization as compared with CON (p < .001). Further, greater mGlu5 receptor availability at baseline (p = .003) and post-test (p = .005) was significantly associated with expression of the SEFL phenotype. Notably, FE female rats displayed a shift to more passive coping (ie, freezing), and displayed greater SEFL susceptibility (p = .01), and had lower baseline mGlu5 availability (p = .03) relative to their FE male rat counterparts. Conclusion: Results are consistent with clinical findings of higher mGlu5 receptor availability in PTSD, and add to growing evidence implicating these receptors in the pathophysiology of PTSD and sex-differences in susceptibility for this disorder.

Nicotine Use and Metabotropic Glutamate Receptor 5 in Individuals With Major Depressive and Posttraumatic Stress Disorders.

Metabotropic glutamate receptor 5 (mGluR5) dysregulation has been implicated in the pathophysiology of many psychiatric disorders, as well as nicotine use and dependence. We used positron emission tomography with [18F]FPEB to measure mGluR5 availability in vivo in 6 groups: (1) nicotine users (NUs) without other psychiatric comorbidities (n = 23); (2) comparison controls (CCs) without nicotine use or psychiatric comorbidities (n = 38); (3) major depressive disorder subjects with concurrent nicotine use (MDD-NU; n = 19); (4) MDD subjects without concurrent nicotine use (MDD-CC; n = 20); (5) posttraumatic stress disorder subjects with concurrent nicotine use (PTSD-NU; n = 17); and (6) PTSD subjects without concurrent nicotine use (PTSD-CC; n = 16). The goal of the study was to test the hypothesis that mGluR5 availability in key corticolimbic regions of interest (ROIs) is different in NU with versus without comorbid psychiatric disorders (ROI: dorsolateral prefrontal cortex [dlPFC], orbitofrontal cortex [OFC], ventromedial prefrontal cortex [vmPFC], anterior cingulate cortex [ACC], amygdala, hippocampus). We found that NU had 11%-13% lower mGluR5 availability in OFC, vmPFC, dlPFC, and ACC as compared with CC, while PTSD-NU had 9%-11% higher mGluR5 availability in OFC, dlPFC, and ACC compared with PTSD. Furthermore, relationships between mGluR5 availability and psychiatric symptoms varied as a function of psychiatric diagnosis among NUs. NU showed a negative correlation between mGluR5 and smoking cravings and urges (r's = -0.58 to -0.70, p's = 0.011 - 0.047), while PTSD-NU had the reverse relationship (r's = 0.60-0.71, p's = 0.013-0.035 in ACC, vmPFC, and dlPFC). These findings have substantial implications for our understanding of glutamate homeostasis in psychiatric subgroups and for identifying key neural phenotypes among NU. mGluR5 is a potential treatment target for precision medicine in individuals with nicotine use.

Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [18F]FPEB and positron emission tomography study in rats.

Clinical investigations suggest involvement of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of fear learning that underlies trauma-related disorders. Here, we utilized a 4-day fear learning paradigm combined with positron emission tomography (PET) to examine the relationship between mGluR5 availability and differences in the response of rats to repeated footshock exposure (FE). Specifically, on day 1, male (n = 16) and female (n = 12) rats received 15 footshocks and were compared with control rats who did not receive footshocks (n = 7 male; n = 4 female). FE rats were classified as low responders (LR) or high responders (HR) based on freezing to the context the following day (day 2). PET with [18F]FPEB was used to calculate regional mGluR5 binding potential (BPND) at two timepoints: prior to FE (i.e., baseline), and post-behavioral testing. Additionally, we used an unbiased proteomics approach to assess group and sex differences in prefrontal cortex (PFC) protein expression. Post-behavioral testing we observed decreased BPND in LR females, but increased BPND in HR males relative to baseline. Further, individuals displaying the greatest freezing during the FE context memory test had the largest increases in PFC BPND. Males and females displayed unique post-test molecular profiles: in males, the greatest differences were between FE and CON, including upregulation of mGluR5 and related molecular networks in FE, whereas the greatest differences among females were between the LR and HR groups. These findings suggest greater mGluR5 availability increases following footshock exposure may be related to greater contextual fear memory. Results additionally reveal sex differences in the molecular response to footshock, including differential involvement of mGluR5-related molecular networks.

Differences in Quantification of the Metabotropic Glutamate Receptor 5 Across Bipolar Disorder and Major Depressive Disorder.

BACKGROUND: Understanding the neurobiology underlying bipolar disorder (BD) versus major depressive disorder (MDD) is crucial for accurate diagnosis and for driving the discovery of novel treatments. A promising target is the metabotropic glutamate receptor 5 (mGluR5), a modulator of glutamate transmission associated with synaptic plasticity. We measured mGluR5 availability in individuals with MDD and BD for the first time using positron emission tomography. METHODS: Individuals with BD (n = 17 depressed; n = 10 euthymic) or MDD (n = 17) and healthy control (HC) individuals (n = 18) underwent imaging with [18F]FPEB positron emission tomography to quantify mGluR5 availability in regions of the prefrontal cortex, which was compared across groups and assessed in relation to depressive symptoms and cognitive function. RESULTS: Prefrontal cortex mGluR5 availability was significantly different across groups (F6,116 = 2.18, p = .050). Specifically, mGluR5 was lower in BD versus MDD and HC groups, with no difference between MDD and HC groups. Furthermore, after dividing the BD group, mGluR5 was lower in both BD-depression and BD-euthymia groups versus both MDD and HC groups across regions of interest. Interestingly, lower dorsolateral prefrontal cortex mGluR5 was associated with worse depression in MDD (r = -0.67, p = .005) but not in BD. Significant negative correlations were observed between mGluR5 and working memory in MDD and BD-depression groups. CONCLUSIONS: This work suggests that mGluR5 could be helpful in distinguishing BD and MDD as a possible treatment target for depressive symptoms in MDD and for cognitive alterations in both disorders. Further work is needed to confirm differentiating roles for mGluR5 in BD and MDD and to probe modulation of mGluR5 as a preventive/treatment strategy.

Lower synaptic density is associated with psychiatric and cognitive alterations in obesity.

Obesity is a serious medical condition that often co-occurs with stress-related psychiatric disorders. It is recognized that the brain plays a key role in the (patho)physiology of obesity and that there is a bidirectional relationship between obesity and psychopathology, yet molecular mechanisms altered in obesity have not been fully elucidated. Thus, we investigated relationships between obesity and synaptic density in vivo using the radioligand [11C]UCB-J (which binds to synaptic glycoprotein SV2A) and positron emission tomography in individuals with obesity, and with or without stress-related psychiatric disorders. Regions of interest were the dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial, amygdala, hippocampus, and cerebellum. Forty individuals with a body mass index (BMI) ≥ 25 kg/m2 (overweight/obese), with (n = 28) or without (n = 12) psychiatric diagnosis, were compared to 30 age- and sex-matched normal weight individuals (BMI < 25), with (n = 14) or without (n = 16) psychiatric diagnosis. Overall, significantly lower synaptic density was observed in overweight/obese relative to normal weight participants (ηp2 = 0.193, F = 2.35, p = 0.042). Importantly, in participants with stress-related psychiatric diagnoses, we found BMI to be negatively correlated with synaptic density in all regions of interest (p ≤ 0.03), but no such relationship observed for mentally healthy controls (p ≥ 0.68). In the stress-related psychiatric groups, dorsolateral prefrontal cortex synaptic density was negatively associated with measures of worry (r = -0.46, p = 0.01), tension/anxiety (r = -0.38, p = 0.04), fatigue (r = -0.44, p = 0.02), and attentional difficulties (r = -0.44, p = 0.02). In summary, the findings of this novel in vivo experiment suggest compounding effects of obesity and stress-related psychopathology on the brain and the associated symptomatology that may impact functioning. This offers a novel biological mechanism for the relationship between overweight/obesity and stress-related psychiatric disorders that may guide future intervention development efforts.

Risk and resilience factors associated with traumatic loss-related PTSD in U.S. military veterans: Results from the National Health and Resilience in Veterans Study.

PURPOSE: Sudden death of a loved one is the most prevalent potentially traumatic event worldwide, yet little is known about risk and resilience factors associated with traumatic loss-related posttraumatic stress disorder (PTSD). METHODS: Data from a nationally representative sample of U.S. military veterans were analyzed to identify sociodemographic, military, health and psychosocial correlates of traumatic loss-related PTSD. RESULTS: Loneliness, somatic symptoms, and attachment style were the strongest correlates of PTSD symptom severity and positive screens for traumatic loss-related PTSD. CONCLUSION: Loneliness, somatic symptoms, and attachment style may represent therapeutic targets to help mitigate traumatic loss-related PTSD in U.S. veterans.

Polygenic risk for traumatic loss-related PTSD in US military veterans: Protective effect of secure attachment style.

OBJECTIVES: To examine whether attachment style moderates the relationship between polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) re-experiencing (PTSDREX) symptoms and the severity of and positive screen for traumatic loss-related PTSD. METHODS: Data were analysed from 631 US veterans who endorsed 'unexpected death of a loved one' as their 'worst' traumatic event. Multivariable models evaluated the association between PRS for PTSDREX, attachment style, and their interaction in predicting severity and positive screen for PTSD. A gene enrichment analysis was conducted to identify possible molecular mechanisms underlying the association between PTSDREX PRS and PTSD. RESULTS: PTSDREX PRS (ß = 0.17; odds ratio [OR] = 1.85), attachment style (ß= -0.33; OR = 0.14), and PTSDREX PRS × attachment style interaction (ß= -0.12; OR = 0.53) were significant predictors of the severity and positive screen for PTSD. The most significant gene set detected was the gene ontology (GO) cellular component podosome set (GO:0002102, p < 3.95 × 10-5). CONCLUSIONS: Having a secure attachment style may help mitigate polygenic risk for developing traumatic loss-related PTSD in US veterans. Podosomes, which are implicated in inflammatory and neuroplasticity processes, may contribute to the genetic liability to developing loss-related PTSD. Psychological treatments targeting attachment security may help mitigate increased polygenic risk for loss-related PTSD in this population.

Role of polyunsaturated fatty acids in human brain structure and function across the lifespan: An update on neuroimaging findings.

There is a substantial body of evidence from animal studies implicating polyunsaturated fatty acids (PUFA) in neuroinflammatory, neurotrophic, and neuroprotective processes in brain. However, direct evidence for a role of PUFA in human brain structure and function has been lacking. Over the last decade there has been a notable increase in neuroimaging studies that have investigated the impact of PUFA intake and/or blood levels (i.e., biostatus) on brain structure, function, and pathology in human subjects. The majority of these studies specifically evaluated associations between omega-3 PUFA intake and/or biostatus and neuroimaging outcomes using a variety of experimental designs and imaging techniques. This review provides an updated overview of these studies in an effort to identify patterns to guide and inform future research. While the weight of evidence provides general support for a beneficial effect of a habitual diet consisting of higher omega-3 PUFA intake on cortical structure and function in healthy human subjects, additional research is needed to replicate and extend these findings as well as identify response mediators and clarify mechanistic pathways. Controlled intervention trials are also needed to determine whether increasing n-3 PUFA biostatus can prevent or attenuate neuropathological brain changes observed in patients with or at risk for psychiatric disorders and dementia.

Effects of dietary-induced alterations in rat brain docosahexaenoic acid accrual on phospholipid metabolism and mitochondrial bioenergetics: An in vivo31P MRS study.

Evidence from 31P magnetic resonance spectroscopy (31P MRS) studies suggest that different psychiatric disorders, which typically emerge during adolescence and young adulthood, are associated with abnormalities in mitochondrial bioenergetics and membrane phospholipid metabolism. These disorders are also associated with deficits in omega-3 polyunsaturated fatty acids (n-3 PUFA), including docosahexaenoic acid (DHA) which accumulates in mitochondrial and synaptic membranes. The present study investigated the effects of dietary-induced alterations in brain DHA accrual during adolescence on phospholipid metabolism and bioenergetics in the adult rat brain using 31P MRS. During the peri-adolescent period (P21-P90), male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (18:3n-3, n = 20). On P90, 31P MRS was performed under isoflurane anesthetic using a 7 T Bruker Biospec system. Compared with controls, brain DHA levels were significantly lower in adult rats fed the DEF diet (-17%, p ≤ 0.0001) and significantly higher in rats fed the FO diet (+14%, p ≤ 0.0001). There were no significant group differences for indices of bioenergetics, including adenosine triphosphate and phosphocreatine levels, or indices of membrane phospholipid metabolism including phosphomonoesters and phosphodiesters. Therefore, the present 31P MRS data suggest that rat brain DHA levels are not a significant predictor of mitochondrial bioenergetics or membrane phospholipid metabolism.

Glutamate homeostasis in the adult rat prefrontal cortex is altered by cortical docosahexaenoic acid accrual during adolescence: An in vivo1H MRS study.

Major psychiatric disorders are associated with dysregulated glutamate homeostasis and deficits in the omega-3 fatty acid docosahexaenoic acid (DHA). This study determined the effects of dietary-induced alterations in brain DHA accrual on cortical glutamate homeostasis in the adult rat brain. Adolescent rats were fed a control diet (n = 20), a n-3 fatty acid-deficient diet (DEF, n = 20), or a fish oil-fortified diet containing preformed DHA (FO, n = 20). In adulthood 1H MRS scans were performed with voxels in the prefrontal cortex (PFC) and thalamus. Compared with controls, erythrocyte, PFC, and thalamus DHA levels were significantly lower in DEF rats and significantly higher in FO rats. In the PFC, but not the thalamus, glutamate was significantly elevated in DEF rats compared with controls and FO rats. Glutamine did not differ between groups and the glutamine/glutamate ratio was lower in DEF rats. No differences were observed for markers of excitotoxicity (NAA, GFAP), or astrocyte glutamate transporter (GLAST, GLT-1) or glutamine synthetase expression. Across diet groups, PFC DHA levels were inversely correlated with PFC glutamate levels and positively correlated with GLAST expression. Together these findings demonstrate that rat cortical DHA accrual during adolescence impacts glutamate homeostasis in the adult PFC.