Quality of early-life maternal care predicts empathy-like behavior in adult male rats: linking empathy to BDNF gene expression in associated brain regions

Fetal growth restriction is associated with reduced pancreatic β-cell mass, contributing to impaired glucose tolerance and diabetes. Exercise training increases β-cell mass in animals with diabetes and has long-lasting metabolic benefits in rodents and humans. We studied the effect of exercise training on islet and β-cell morphology and plasma insulin and glucose, following an intraperitoneal glucose tolerance test (IPGTT) in juvenile and adult male Wistar-Kyoto rats born small. Bilateral uterine vessel ligation performed on day 18 of pregnancy resulted in Restricted offspring born small compared with sham-operated Controls and also sham-operated Reduced litter offspring that had their litter size reduced to five pups at birth. Restricted, Control, and Reduced litter offspring remained sedentary or underwent treadmill running from 5 to 9 or 20 to 24 wk of age. Early life exercise increased relative islet surface area and β-cell mass across all groups at 9 wk, partially restoring the 60–68% deficit ( P < 0.05) in Restricted offspring. Remarkably, despite no further exercise training after 9 wk, β-cell mass was restored in Restricted at 24 wk, while sedentary littermates retained a 45% deficit ( P = 0.05) in relative β-cell mass. Later exercise training also restored Restricted β-cell mass to Control levels. In conclusion, early life exercise training in rats born small restored β-cell mass in adulthood and may have beneficial consequences for later metabolic health and disease.

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SUN-235 Deficient Fear Extinction in PRKAR1A-Defective Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1855 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Margaret Keil ◽

Enrica Paradiso ◽

Rita S Keil ◽

Maddalena Ugolini ◽

Evan Harris ◽

...

Keyword(s):

Gene Expression ◽

Fear Conditioning ◽

Conditioned Fear ◽

Critical Role ◽

Fear Memory ◽

Brain Regions ◽

Fear Extinction ◽

Carney Complex ◽

Bdnf Gene ◽

Extinction Learning

Abstract Background: The role of the cAMP/PKA signaling in molecular pathways involved in fear memory is well established: PKA is required for fear memory formation and is a constraint for fear extinction. Previously we reported that a Prkar1a heterozygote (HZ) mouse that was developed in our lab to investigate Carney complex (CNC), the disease caused by PRKAR1A mutations, showed brain region-specific increased PKA activity that was associated with anxiety-like behavioral phenotype and threat bias (Keil, 2010, 2013). We hypothesized that Prkar1a+/- (HZ) mice would have deficits in fear extinction behavior. Brain derived neurotrophic factor (BDNF) has a critical role in formation of fear memory and its transcription is regulated by PKA/CREB. A mouse model with down regulation of PKA provides an opportunity for the first time to investigate the effect of altered PKA signaling on fear conditioning and extinction. Method: Fear conditioning, fear extinction learning, and fear extinction recall were tested in adult male HZ and wild-type (WT) mice as follows: fear conditioning training followed 24hr later by extinction training (new context), then 24hr later by extinction recall training. Percentage of time freezing was used to assess conditioned fear response. We measured BDNF gene expression in brain regions after completion of extinction recall training. Results: As expected, fear conditioning (learning) behavior was similar in HZ and WT mice. However, HZ mice showed a significant deficit in the early phase of fear extinction learning compared to WT. There was no difference in extinction recall between genotypes. Alterations in BDNF gene expression in the prefrontal cortex and amygdala was associated with deficit in fear extinction. Conclusion: Mice with a downregulation of Prkar1a gene demonstrate intact fear conditioning but impaired fear extinction learning, consistent with prior studies that report that PKA inhibition is necessary to facilitate extinction learning. Prkar1a+/- mice provide a valuable model to investigate impaired fear extinction to identify mechanisms for therapeutic targets for anxiety and trauma-related disorders.

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Effects of Maternal Deprivation on the Prefrontal Cortex of Male Rats: Cellular, Neurochemical, and Behavioral Outcomes

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.666547 ◽

2021 ◽

Vol 15 ◽

Author(s):

Joko Poleksic ◽

Milan Aksic ◽

Slobodan Kapor ◽

Dubravka Aleksic ◽

Tihomir Stojkovic ◽

...

Keyword(s):

Prefrontal Cortex ◽

Young Adult ◽

Adult Male ◽

Early Life ◽

Microglial Activation ◽

Maternal Deprivation ◽

Male Rats ◽

Orbital Cortex ◽

Deep Layers ◽

Rostral Part

Stressful events experienced during early life are associated with increased vulnerability of developing psychopathology in adulthood. In the present study, we exposed 9-day-old Wistar rats to 24 h maternal deprivation (MD) with the aim to investigate the impact of early life stress (ELS) on morphological, biochemical, and functional aspects of the prefrontal cortex (PFC), a brain region particularly sensitive to stress. We found that in the superficial medial orbital cortex (MO), young adult male rats had reduced density of GAD67 and CCK immunopositive cells, while the rostral part of the ventral lateral orbital cortex (roVLO) showed a decrease in the density of GAD67 immunopositive cells in both superficial and deep layers. In addition, the superficial rostral part of area 1 of the cingulate cortex (roCg1) and deep prelimbic cortex (PrL) was also affected by MD indicated by the reduction in PV immunopositive cellular density. Furthermore, MD induced upregulation of brain-derived neurotrophic factor (BDNF), while it did not affect the overall expression of Iba1 in neonatal or young adult PFC as measured by Western blot, however, microglial activation in young adult MD rats was detected immunohistochemically in deep layers of MO and infralimbic cortex (IL). Interestingly, when young adult male rats were subjected to a behavioral flexibility test in a T-maze, MD rats showed a subtle impairment in T-maze reversal learning indicating a mildly affected PFC function. Taken together, our findings demonstrated that MD reduced the density of interneurons and induced microglial activation, in particular, PFC areas at young adulthood, and could alter synaptic plasticity accompanied by PFC dysfunction.

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Long-Term Decreases in the Expression of Calcineurin and GABAA Receptors Induced by Early Maternal Separation Are Associated with Increased Anxiety-Like Behavior in Adult Male Rats

Developmental Neuroscience ◽

10.1159/000512221 ◽

2020 ◽

pp. 1-10

Author(s):

Maryam Mahmoodkhani ◽

Maedeh Ghasemi ◽

Leila Derafshpour ◽

Mohammad Amini ◽

Nasrin Mehranfard

Keyword(s):

Anxiety Disorders ◽

Glutamate Receptors ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Central Area ◽

Early Life Stress ◽

Brain Regions ◽

Male Rats ◽

Lower Percentage

Introduction: Early life stress is a well-described risk factor of anxiety disorders in adulthood. Dysfunction in GABA/glutamate receptors and their functional regulator, calcineurin, is linked to anxiety disorders. Here, we investigated the effect of early life stress, such as repeated maternal separation (MS; 3 h per day from postnatal day [P] 2 to 11), on changes in the expression of calcineurin as well as the ionotropic glutamatergic and GABAergic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) and GABAA receptors in the hippocampus and prefrontal cortex (PFC) of adolescent (P35) and adult (P62) male Wistar rats and their correlations with anxiety-like behavior in adulthood. Methods: The protein levels were assessed by Western blot analysis. Anxiety-like behavior was measured in the elevated plus maze (EPM) and open field (OF) tests. Results: MS induced a regional transient decrease of glutamate receptors expression at P35, with decreased NMDA and AMPA receptor levels, respectively, in the hippocampus and PFC, suggesting a possible decrease in excitatory synaptic strength. In contrast to glutamate receptors, MS had long-lasting influence on GABAA receptor and calcineurin levels, with reduced expression of GABAA receptor and calcineurin in both brain regions at P35 that continued into adulthood. These results were accompanied by increased anxiety behavior in adulthood, shown by lower percentage of number of total entries and time spent in the open arms of the EPM, and by lower time spent and number of entries in the OF central area. Conclusions: Together, our study suggests that GABAA receptors via calcineurin-dependent signaling pathways may play an important role in the expression of stress-induced anxiety-like behavior.

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