The Impact Of Neonatal Pain And Reduced Maternal Care On Brain And Behavioral Development

In the neonatal intensive care unit (NICU) preterm infants are exposed to a multitude of stressors, which include both neonatal pain and reduced maternal care. Clinical and preclinical research has demonstrated that exposure to neonatal pain and reduced maternal care has a profound negative impact on brain and behavioral development. Currently, the biological mechanism by which both of these stressors impacts brain and behavioral outcomes remains widely unknown. To uncover a potential biological mechanism, the current dissertation project utilized a preclinical model of repetitive needle pokes and developed a novel model of reduced maternal care through tea-ball encapsulation. Briefly, rat pups were separated into one of five groups: touch control, isolation and touch, pain, pain and isolation, and unhandled controls. Pups in the isolation conditions were enclosed in tea-ball infusers from postnatal day (PD) 1-4, four times a day for 30 minutes. Pups in pain conditions experienced repetitive needle pokes into alternating paws starting on PD1 and ending on PD4. Unhandled control pups were left undisturbed throughout each experiment. For experiment 1, pups were sacrificed immediately after the last tea-ball exposure on PD4 and serum corticosterone and various brain metabolites were analyzed. We observed a significant increase in serum corticosterone on PD4 in maternally isolated animals and a non-significant increase in pain exposed animals. Further, glutamate/creatine ratios were reduced in the frontal cortex and hippocampus in pain and maternally isolated animals respectively. For experiment 2, pups matured into adulthood and affective and cognitive behaviors were assessed through the open field test, novel object recognition test, Morris water maze, and restraint stress testing. During the Morris water maze, pain exposed animals displayed accelerated learning but both stressors impaired long-term memory. Moreover, reversal learning was enhanced in male isolated animals compared to touch males and isolated females. Finally, female pain exposed animals displayed impaired HPA-axis recovery following an acute stressor. Collectively, these studies demonstrate that both neonatal pain and reduced maternal care are potent neonatal stressors and can influence neonatal neurochemistry and adult cognitive and HPA-axis functioning. These findings highlight the need of interventions mitigating neonatal stress in the NICU

Genetic Differences in Dorsal Hippocampus Acetylcholinesterase Activity Predict Contextual Fear Learning Across Inbred Mouse Strains.

Learning is a critical behavioral process that is influenced by many neurobiological systems. We and others have reported that acetylcholinergic signaling plays a vital role in learning capabilities, and it is especially important for contextual fear learning. Since cholinergic signaling is affected by genetic background, we examined the genetic relationship between activity levels of acetylcholinesterase (AChE), the primary enzyme involved in the acetylcholine metabolism, and learning using a panel of 20 inbred mouse strains. We measured conditioned fear behavior and AChE activity in the dorsal hippocampus, ventral hippocampus, and cerebellum. Acetylcholinesterase activity varied among inbred mouse strains in all three brain regions, and there were significant inter-strain differences in contextual and cued fear conditioning. There was an inverse correlation between fear conditioning outcomes and AChE levels in the dorsal hippocampus. In contrast, the ventral hippocampus and cerebellum AChE levels were not correlated with fear conditioning outcomes. These findings strengthen the link between acetylcholine activity in the dorsal hippocampus and learning, and they also support the premise that the dorsal hippocampus and ventral hippocampus are functionally discrete

The Antidepressant Drugs Fluoxetine and Duloxetine Produce Anxiolytic-Like Effects in a Schedule-Induced Polydipsia Paradigm in Ratsenhancement of Fluoxetine\u27s Effects by the Α2 Adrenoceptor Antagonist Yohimbine

Similar to the time-course for treating depression, several weeks of administration are required for serotonin (5-HT) reuptake inhibitors to produce anxiolytic effects. Previous studies with the schedule-induced polydipsia paradigm (a putative preclinical anxiety model) have shown that repeated administration of antidepressant drugs is necessary to produce a suppression of polydipsia, which is interpreted as an anxiolytic-like effect. The present study sought to expand past findings by evaluating the selective 5-HT reuptake inhibitor (SSRI) fluoxetine and the 5-HT-norepinephrine reuptake inhibitor duloxetine in the schedule-induced polydipsia paradigm with rats. Dose combinations of the α2 adrenoceptor antagonist yohimbine with fluoxetine were also explored to determine whether α 2 adrenoceptor antagonism could enhance the anxiolytic-like effects produced by an SSRI. Fluoxetine and duloxetine significantly reduced water intake over the course of daily administrations. Daily treatment with the combination of fluoxetine and yohimbine produced a significantly greater reduction in water intake than fluoxetine alone. The present results confirmed previous findings that inhibition of 5-HT reuptake reduces water consumption in this paradigm. The results for the α 2 antagonist yohimbine (in combination with fluoxetine) also indicate that α2 adrenoceptor antagonism may significantly enhance anxiolytic-like effects of SSRIs