Dopaminergic lesions of the anterior cingulate cortex of rats increase vulnerability to salient distractors.

The anterior cingulate cortex (ACC) has been shown to be critical to many aspects of executive function including filtering irrelevant information, updating response contingencies when reinforcement contingencies change and stabilizing task sets. Nonspecific lesions to this region in rats produce a vulnerability to distractors that have gained salience through prior associations with reinforcement. These lesions also exacerbate cognitive fatigue in tests of sustained attention but do not produce global attentional impairments nor do they produce distractibility to novel distractors that do not have a prior association with reinforcement. To determine the neurochemical basis of these cognitive impairments, dopaminergically selective lesions of the ACC were made in both male and female Long-Evans, hooded rats prior to assessment in two attentional tasks. Dopaminergic lesions of the ACC increase the vulnerability of subjects to previously reinforced distractors and impede formation of an attentional set. Lesioned rats were not more susceptible to the effects of novel, irrelevant stimuli in a test of sustained attention as has been previously shown. Additionally, the effects of dopaminergic lesions were found to differ based on sex. Lesioned female, but not male, rats were more vulnerable than sham-lesioned females to the effects of prolonged testing and the removal of reinforcement during a test of sustained attention. Together, these data support the hypothesis that dopamine in the ACC is critical to filtering distractors whose salience has been gained through reinforcement.

Evidence for a role of corticopetal, noradrenergic systems in the development of executive function.

Adolescence is a period during which many aspects of executive function are maturing. Much of the literature has focused on discrepancies between sub-cortical and cortical development that is hypothesized to lead to over-processing of reinforcement related stimuli unchecked by fully matured response inhibition. Specifically, maturation of sub-cortical dopaminergic systems that terminate in the nucleus accumbens has been suggested to occur prior to the full maturation of corticopetal dopaminergic systems. However, converging evidence supports the hypothesis that many aspects of cognitive control are critically linked to cortical noradrenergic systems, that the effectiveness of drugs used to treat disorders of executive function, e.g. ADHD, may result primarily from increases in cortical norepinephrine (NE) and that cortical noradrenergic systems mature across adolescence. However, little attention has been given to the development of this system during adolescence or to its influence in executive function. In the present paper, we discuss the developmental trajectory of the noradrenergic system of the forebrain, highlight the interactions between noradrenergic and dopaminergic systems, and highlight the contribution of the immature corticopetal noradrenergic systems in the ontogeny of several aspects of executive function. Finally we compare data from adolescent rats to those gathered after selective depletion of NE in sub-regions of the prefrontal cortex with an emphasis on the similarities in performance of NE lesioned rats and adolescents.

Prenatal malnutrition leads to deficits in attentional set shifting and decreases metabolic activity in prefrontal subregions that control executive function.

Globally, over 25% of all children under the age of 5 years experience malnutrition leading to cognitive and emotional impairments that can persist into adulthood and beyond. We use a rodent model to determine the impact of prenatal protein malnutrition on executive functions in an attentional set-shifting task and metabolic activity in prefrontal cortex (PFC) subregions critical to these behaviors. Long-Evans dams were provided with a low (6% casein) or adequate (25% casein) protein diet 5 weeks before mating and during pregnancy. At birth, the litters were culled to 8 pups and fostered to control dams on the 25% casein diet. At postnatal day 90, prenatally malnourished rats were less able to shift attentional set and reverse reward contingencies than controls, demonstrating cognitive rigidity. Naive same-sexed littermates were assessed for regional brain activity using the metabolic marker (14)C-2-deoxyglucose (2DG). The prenatally malnourished rats had lower metabolic activity than controls in prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices, but had comparable activity in the nearby piriform cortex and superior colliculus. This study demonstrates that prenatal protein malnutrition in a well-described animal model produces cognitive deficits in tests of attentional set shifting and reversal learning, similar to findings of cognitive inflexibility reported in humans exposed to early childhood malnutrition.

In vivo microdialysis shows differential effects of prenatal protein malnutrition and stress on norepinephrine, dopamine, and serotonin levels in rat orbital frontal cortex.

Prenatal protein malnutrition (PPM) alters the developing brain including changes in monoaminergic systems and attention. In the present study, we used in vivo microdialysis to examine the relationship between PPM, acute stress, and extracellular serotonin (5HT), dopamine (DA) and norepinephrine (NE) in both hemispheres of lateral orbital frontal cortices (lOFC) in the adult rat. We hypothesized that prenatal protein malnutrition would alter extracellular concentrations of cortical monoamines. The effects of an acute restraint stress were also assessed because PPM alters the brain's response to stress. We used adult male, Long-Evans rats [10 prenatally malnourished (6% casein) and 10 prenatally well-nourished (25% casein)]. Samples were collected from the left and right hemispheres of the lOFC every 20 min for 6 hr total and quantified using high-performance liquid chromatography (HPLC). After 2 hr of sampling, animals were exposed to a 40-min restraint stress. Extracellular levels of NE were significantly higher in PPM animals than in well-nourished controls across both hemispheres at all time-points. In contrast, baseline levels of 5HT and DA levels did not differ between nutritional groups. 5HT levels, but not NE or DA levels, were elevated compared to baseline levels in both nutritional groups and in both hemispheres during the first 20 min of stress exposure. These data highlight the impact of PPM on neuromodulatory systems and the profile of changes in response to acute stress. Additional studies are needed to determine how these basal and stress-related responses impact cognitive performance and whether these differences persist during cognitive testing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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.

Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats.

Adolescence is a period of major behavioral and brain reorganization. As diagnoses and treatment of disorders like attention deficit hyperactivity disorder (ADHD) often occur during adolescence, it is important to understand how the prefrontal cortices change and how these changes may influence the response to drugs during development. The current study uses an adolescent rat model to study the effect of standard ADHD treatments, atomoxetine and methylphenidate on attentional set shifting and reversal learning. While both of these drugs act as norepinephrine reuptake inhibitors, higher doses of atomoxetine and all doses of methylphenidate also block dopamine transporters (DAT). Low doses of atomoxetine, were effective at remediating cognitive rigidity found in adolescents. In contrast, methylphenidate improved performance in rats unable to form an attentional set due to distractibility but was without effect in normal subjects. We also assessed the effects of GBR 12909, a selective DAT inhibitor, but found no effect of any dose on behavior. A second study in adolescent rats investigated changes in norepinephrine transporter (NET) and dopamine beta hydroxylase (DBH) density in five functionally distinct sub-regions of the prefrontal cortex: infralimbic, prelimbic, anterior cingulate, medial and lateral orbitofrontal cortices. These regions are implicated in impulsivity and distractibility. We found that NET, but not DBH, changed across adolescence in a regionally selective manner. The prelimbic cortex, which is critical to cognitive rigidity, and the lateral orbitofrontal cortex, critical to reversal learning and some forms of response inhibition, showed higher levels of NET at early than mid- to late adolescence. This article is part of a Special Issue entitled SI: Noradrenergic System.

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition.

BACKGROUND: Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored. METHODS: We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the first year of life for moderate to severe protein-energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study. Attention deficits and cognitive performance were evaluated with the Connors Adult Attention Rating Scale and Wechsler Abbreviated Scale of Intelligence. Expression of nutrition-sensitive genes was explored by quantitative reverse transcriptase polymerase chain reaction in rat prefrontal cortex. RESULTS: We identified 134 nutrition-sensitive, differentially methylated genomic regions, with most (87%) specific for generation 1. Multiple neuropsychiatric risk genes, including COMT, IFNG, MIR200B, SYNGAP1, and VIPR2 showed associations of specific methyl-CpGs with attention and IQ. IFNG expression was decreased in prefrontal cortex of rats showing attention deficits after developmental malnutrition. CONCLUSIONS: Early childhood malnutrition entails long-lasting epigenetic signatures associated with liability for attention and cognition, and limited potential for intergenerational transmission.

Cognitive control and the anterior cingulate cortex: how conflicting stimuli affect attentional control in the rat.

Converging evidence supports the hypothesis that the prefrontal cortex is critical for cognitive control. One prefrontal subregion, the anterior cingulate cortex, is hypothesized to be necessary to resolve response conflicts, disregard salient distractors and alter behavior in response to the generation of an error. These situations all involve goal-oriented monitoring of performance in order to effectively adjust cognitive processes. Several neuropsychological disorders, e.g., schizophrenia, attention deficit hyperactivity and obsessive compulsive disorder, are accompanied by morphological changes in the anterior cingulate cortex. These changes are hypothesized to underlie the impairments on tasks that require cognitive control found in these subjects. A novel conflict monitoring task was used to assess the effects on cognitive control of excitotoxic lesions to anterior cingulate cortex in rats. Prior to surgery all subjects showed improved accuracy on the second of two consecutive, incongruent trials. Lesions to the anterior cingulate cortex abolished this. Lesioned animals had difficulty in adjusting cognitive control on a trial-by-trial basis regardless of whether cognitive changes were increased or decreased. These results support a role for the anterior cingulate cortex in adjustments in cognitive control.

Interaction of age, cognitive function, and gait performance in 50-80-year-olds.

The variability of walking gait timing increases with age and is strongly related to fall risk. The purpose of the study was to examine the interaction of age, cognitive function, and gait performance during dual-task walking. Forty-two, healthy men and women, 50-80 years old, completed the Mini-Mental State Exam (MMSE) and Trail Making Test (TMT) to assess cognitive performance and were separated into groups by decade of life. They then performed dual-task walking, at a self-selected pace, on an instrumented treadmill during three cognitive loading conditions: (1) no cognitive load, (2) subtraction from 100 by 1s, and (3) subtraction from 100 by 3s. The treadmill recorded spatiotemporal gait parameters that were used to calculate the mean and coefficient of variation for each variable over ten strides. Time to complete the TMT was positively correlated with age, stride time, double-limb support time, and mediolateral instability and was inversely correlated with single-limb support time. Subjects in their 70s increased their stride time and double-limb support time during the most challenging dual-task condition (subtraction by 3s), whereas subjects in their 50s and 60s did not. Across conditions, the variability of stride length, stride time, and single-limb support time was greatest in the 70s. Mediolateral instability increased only for subjects in their 70s in the subtraction by 3s condition. Reduced cognitive function with age makes it difficult for older adults to maintain a normal, rhythmical gait pattern while performing a cognitive task, which may place them at greater risk for falling.

Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of noradrenergic α1 - and α2-receptors.

BACKGROUND: Psychostimulants improve a variety of cognitive and behavioral processes in patients with attention-deficit/hyperactivity disorder (ADHD). Limited observations suggest a potentially different dose-sensitivity of prefrontal cortex (PFC)-dependent function (narrow inverted-U-shaped dose-response curves) versus classroom/overt behavior (broad inverted U) in children with ADHD. Recent work in rodents demonstrates that methylphenidate (MPH; Ritalin) elicits a narrow inverted-U-shaped improvement in performance in PFC-dependent tests of working memory. The current studies first tested the hypothesis that PFC-dependent tasks, in general, display narrow dose sensitivity to the beneficial actions of MPH. METHODS: The effects of varying doses of MPH were examined on performance of rats in two tests of PFC-dependent cognition, sustained attention and attentional set shifting. Additionally, the effect of pretreatment with the α1-antagonist prazosin (.5 mg/kg) on MPH-induced improvement in sustained attention was examined. RESULTS: MPH produced a broad inverted-U-shaped facilitation of sustained attention and attentional set shifting. Prior research indicates α1-receptors impair, whereas α2-receptors improve, working memory. In contrast, attentional set shifting is improved with α1-receptor activation, whereas α2-receptors exert minimal effects in this task. Given the similar dose sensitivity of sustained attention and attentional set-shifting tasks, additional studies examined whether α1-receptors promote sustained attention, similar to attentional set shifting. In these studies, MPH-induced improvement in sustained attention was abolished by α1-receptor blockade. CONCLUSIONS: PFC-dependent processes display differential sensitivity to the cognition-enhancing actions of psychostimulants that are linked to the differential involvement of α1- versus α2-receptors in these processes. These observations have significant preclinical and clinical implications.

Atomoxetine facilitates attentional set shifting in adolescent rats.

Adolescent rats show immaturities in executive function and are less able than adult rats to learn reinforcement reversals and shift attentional set. These two forms of executive function rely on the functional integrity of the orbitofrontal and prelimbic cortices respectively. Drugs used to treat attention deficit disorder, such as atomoxetine, that increase cortical catecholamine levels improve executive functions in humans, non-human primates and adult rats with prefrontal lesions. Cortical noradrenergic systems are some of the last to mature in primates and rats. Moreover, norepinephrine transporters (NET) are higher in juvenile rats than adults. The underdeveloped cortical noradrenergic system and higher number of NET are hypothesized to underlie the immaturities in executive function found in adolescents. We assessed executive function in male Long-Evans rats using an intra-dimensional/extradimensional set shifting task. We administered the NET blocker, atomoxetine (0.0, 0.1, 0.9 mg/kg/ml; i.p.), prior to the test of attentional set shift and a reinforcement reversal. The lowest dose of drug facilitated attentional set shifting but had no effect on reversal learning. These data demonstrate that NET blockade allows adolescent rats to more easily perform attentional set shifting.