Prenatal Protein Malnutrition Produces Resistance to Distraction Similar to Noradrenergic Deafferentation of the Prelimbic Cortex in a Sustained Attention Task

Exposure to malnutrition early in development increases likelihood of neuropsychiatric disorders, affective processing disorders, and attentional problems later in life. Many of these impairments are hypothesized to arise from impaired development of the prefrontal cortex. The current experiments examine the impact of prenatal malnutrition on the noradrenergic and cholinergic axons in the prefrontal cortex to determine if these changes contribute to the attentional deficits seen in prenatal protein malnourished rats (6% casein vs. 25% casein). Because prenatally malnourished animals had significant decreases in noradrenergic fibers in the prelimbic cortex with spared innervation in the anterior cingulate cortex and showed no changes in acetylcholine innervation of the prefrontal cortex, we compared deficits produced by malnutrition to those produced in adult rats by noradrenergic lesions of the prelimbic cortex. All animals were able to perform the baseline sustained attention task accurately. However, with the addition of visual distractors to the sustained attention task, animals that were prenatally malnourished and those that were noradrenergically lesioned showed cognitive rigidity, i.e., were less distractible than control animals. All groups showed similar changes in behavior when exposed to withholding reinforcement, suggesting specific attentional impairments rather than global difficulties in understanding response rules, bottom-up perceptual problems, or cognitive impairments secondary to dysfunction in sensitivity to reinforcement contingencies. These data suggest that prenatal protein malnutrition leads to deficits in noradrenergic innervation of the prelimbic cortex associated with cognitive rigidity

Prenatal Protein Malnutrition Leads to Hemispheric Differences in the Extracellular Concentrations of Norepinephrine, Dopamine and Serotonin in the Medial Prefrontal Cortex of Adult Rats

Exposure to prenatal protein malnutrition (PPM) leads to a reprogramming of the brain, altering executive functions involving the prefrontal cortex (PFC). In this study we used in vivo microdialysis to assess the effects of PPM on extracellular concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) bilaterally in the ventral portion of the medial prefrontal cortex (vmPFC; ventral prelimbic and infralimbic cortices) of adult Long-Evans rats. Female Long-Evans rats were fed either a low protein (6%) or adequate protein diet (25%) prior to mating and throughout pregnancy. At birth, all litters were culled and fostered to dams fed a 25% (adequate) protein diet. At 120 days of age, 2 mm microdialysis probes were placed into left and right vmPFC. Basal extracellular concentrations of NE, DA, and 5-HT were determined over a 1-h period using HPLC. In rats exposed to PPM there was a decrease in extracellular concentrations of NE and DA in the right vmPFC and an increase in the extracellular concentration of 5-HT in the left vmPFC compared to controls (prenatally malnourished: N = 10, well-nourished: N = 20). Assessment of the cerebral laterality of extracellular neurotransmitters in the vmPFC showed that prenatally malnourished animals had a significant shift in laterality from the right to the left hemisphere for NE and DA but not for serotonin. In a related study, these animals showed cognitive inflexibility in an attentional task. In animals in the current study, NE levels in the right vmPFC of well-nourished animals correlated positively with performance in an attention task, while 5-HT in the left vmPFC of well-nourished rats correlated negatively with performance. These data, in addition to previously published studies, suggest a long-term reprogramming of the vmPFC in rats exposed to PPM which may contribute to attention deficits observed in adult animals exposed to PPM

Cholinergic deafferentation of the entorhinal cortex in rats impairs encoding of novel but not familiar stimuli in a delayed non-match to sample task (DNMS). Program No. 425.4. 2003 Abstract viewer/Itinerary planner

Acetylcholine may regulate working memory for novel stimuli by activating intrinsic mechanisms for sustained spiking in entorhinal cortical neurons, which have been demonstrated in slice preparations of the entorhinal cortex. Computational modeling demonstrates that loss of the cholinergic activation of intrinsic mechanisms for sustained activity could selectively impair working memory for novel stimuli, whereas working memory for familiar stimuli could be maintained because of previously modified synapses. Blockade of muscarinic cholinergic receptors and selective cholinergic lesions has been shown to impair encoding in delayed matching tasks. However, previous studies have not compared explicitly the role of cholinergic modulation in working memory for novel versus familiar stimuli. Here, we show that lesions of the cholinergic innervation of the entorhinal cortex selectively impair delayed nonmatch to sample performance for novel odors, whereas delayed nonmatch to sample for familiar odors is spared. This indicates an important role for cholinergic innervation of the entorhinal cortex in working memory for novel stimuli. Key words: acetylcholine; episodic buffer; sustained activity; computational modeling; working memory; persistent spikin