Impact of supplementation with omega-3 fatty acids after maternal dietary deficiency on adolescent anxiety and microglial morphology.

Dietary maternal deficiency in omega-3 polyunsaturated fatty acids (n-3 PUFA) is a potential risk factor for the development of anxiety and other mood disorders in children and adolescents. Here, we used a previously characterized maternal n-3 PUFA dietary deficiency model in rats to determine the impact of postweaning supplementation on adolescent anxiety-like behaviors. We focused on two models of anxiety: innate anxiety tested by the elevated plus maze and a novel operant model of learned anxiety where animals learn that actions may be associated with a variable probability of harm. Given that recent basic and clinical studies have associated anxiety and other adverse effects of n-3 PUFA deficiency on inflammatory processes and microglial structure and function, we also assessed the impact of our dietary deficiency model and supplementation on adolescent microglial morphology in multiple brain regions. We found that the male and female adolescent n-3 PUFA-deficient groups exhibit increased innate anxiety, but only females showed enhanced learned anxiety. Supplementation after weaning did not significantly affect innate anxiety but ameliorated learned anxiety in females. Thus, the beneficial effects of supplementation on adolescent anxiety may be sex-specific and depend on the type of anxiety. We also found that n-3 PUFA deficiency influences microglia function in adolescents in the amygdala and nigrostriatal, but not mesolimbic, brain regions. Collectively, these data suggest that while n-3 PUFA dietary supplementation may be effective in reducing adolescent anxiety, this effect is context-, sex-, and brain network-specific. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Orbitofrontal and Prelimbic Cortices Serve Complementary Roles in Adapting Reward Seeking to Learned Anxiety.

BACKGROUND: Anxiety is a common symptom of several mental health disorders and adversely affects motivated behaviors. Anxiety can emerge from associating risk of future harm while engaged in goal-guided actions. Using a recently developed behavioral paradigm to model this aspect of anxiety, we investigated the role of 2 cortical subregions, the prelimbic medial frontal cortex (PL) and lateral orbitofrontal cortex (lOFC), which have been implicated in anxiety and outcome expectation, in flexible representation of actions associated with harm risk. METHODS: A seek-take reward-guided instrumental task design was used to train animals (N = 8) to associate the seek action with a variable risk of punishment. After learning, animals underwent extinction training for this association. Fiber photometry was used to measure and compare neuronal activity in the PL and lOFC during learning and extinction. RESULTS: Animals increased action suppression in response to punishment contingencies. This increase dissipated after extinction training. These behavioral changes were associated with region-specific changes in neuronal activity. PL neuronal activity preferentially adapted to the threat of punishment, whereas lOFC activity adapted to safe aspects of the task. Moreover, correlated activity between these regions was suppressed during actions associated with harm risk, suggesting that these regions may guide behavior independently under anxiety. CONCLUSIONS: These findings suggest that the PL and lOFC serve distinct but complementary roles in the representation of learned anxiety. This dissociation may provide a mechanism to explain how overlapping cortical systems are implicated in reward-guided action execution during anxiety.

Elevated α5 integrin expression on myeloid cells in motor areas in amyotrophic lateral sclerosis is a therapeutic target.

Amyotrophic lateral sclerosis (ALS) is a fatal disease affecting upper and lower motor neurons. Microglia directly interact with motor neurons and participate in the progression of ALS. Single-cell mass cytometry (CyTOF) analysis revealed prominent expression of α5 integrin in microglia and macrophages in a superoxide dismutase-1 G93A mouse model of ALS (SOD1G93A). In postmortem tissues from ALS patients with various clinical ALS phenotypes and disease duration, α5 integrin is prominent in motor pathways of the central and peripheral nervous system and in perivascular zones associated with the blood-brain barrier. In SOD1G93A mice, administration of a monoclonal antibody against α5 integrin increased survival compared to an isotype control and improved motor function on behavioral testing. Together, these findings in mice and in humans suggest that α5 integrin is a potential therapeutic target in ALS.