The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

/pdf/how-do-glucocorticoids-influence-stress-responses-4egr3fa2k0.pdf

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes.

Many organisms, especially humans, are characterized by their capacity for intentional, goal-directed actions. However, similar behaviours often proceed automatically, as habitual responses to antecedent stimuli. How are goal-directed actions transformed into habitual responses? Recent work combining modern behavioural assays and neurobiological analysis of the basal ganglia has begun to yield insights into the neural basis of habit formation.

The role of the basal ganglia in habit formation

Converging findings of animal and human studies provide compelling evidence that the amygdala is critically involved in enabling us to acquire and retain lasting memories of emotional experiences. This review focuses primarily on the findings of research investigating the role of the amygdala in modulating the consolidation of long-term memories. Considerable evidence from animal studies investigating the effects of posttraining systemic or intra-amygdala infusions of hormones and drugs, as well as selective lesions of specific amygdala nuclei, indicates that (a) the amygdala mediates the memory-modulating effects of adrenal stress hormones and several classes of neurotransmitters; (b) the effects are selectively mediated by the basolateral complex of the amygdala (BLA); (c) the influences involve interactions of several neuromodulatory systems within the BLA that converge in influencing noradrenergic and muscarinic cholinergic activation; (d) the BLA modulates memory consolidation via efferents to other brain regions, including the caudate nucleus, nucleus accumbens, and cortex; and (e) the BLA modulates the consolidation of memory of many different kinds of information. The findings of human brain imaging studies are consistent with those of animal studies in suggesting that activation of the amygdala influences the consolidation of long-term memory; the degree of activation of the amygdala by emotional arousal during encoding of emotionally arousing material (either pleasant or unpleasant) correlates highly with subsequent recall. The activation of neuromodulatory systems affecting the BLA and its projections to other brain regions involved in processing different kinds of information plays a key role in enabling emotionally significant experiences to be well remembered.

The amygdala modulates the consolidation of memories of emotionally arousing experiences

Stress and cognitive function

The present experiments investigated the role of the prelimbic–infralimbic areas in behavioral flexibility using a place–response learning paradigm. All rats received a bilateral cannula implant aimed at the prelimbic–infralimbic areas. To examine the role of the prelimbic–infralimbic areas in shifting strategies, rats were tested on a place and a response discrimination in a cross-maze. Some rats were tested on the place version first followed by the response version. The procedure for the other rats was reversed. Infusions of 2% tetracaine into the prelimbic–infralimbic areas did not impair acquisition of the place or response discriminations. Prelimbic–infralimbic inactivation did impair learning when rats were switched from one discrimination to the other (cross-modal shift). To investigate the role of the prelimbic–infralimbic areas in intramodal shifts (reversal learning), one group of rats was tested on a place reversal and another group tested on a response reversal. Prelimbic–infralimbic inactivation did not impair place or response intramodal shifts. Some rats that completed testing on a particular version in the cross-modal and intramodal experiments were tested on the same version in a new room for 3 d. The transfer tests revealed that rats use a spatial strategy on the place version and an egocentric response strategy on the response version. Overall, these results suggest that the prelimbic–infralimbic areas are important for behavioral flexibility involving cross-modal but not intramodal shifts.

https://www.jneurosci.org/content/jneuro/19/11/4585.full.pdf

Involvement of the Prelimbic–Infralimbic Areas of the Rodent Prefrontal Cortex in Behavioral Flexibility for Place and Response Learning

Behavioral flexibility refers to the ability to shift strategies or response patterns with a change in environmental contingencies. The frontal lobe and basal ganglia are two brain regions implicated in various components for successfully adapting to changed environmental contingencies. This paper discusses a series of experiments that investigate the contributions of the rat prelimbic area, infralimbic area, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Orbitofrontal cortex inactivation did not impair initial learning of discrimination tests, but it impaired reversal learning due to perseverance in the previously learned choice pattern. Inactivation of the prelimbic area did not affect acquisition or reversal learning of different discrimination tests, but it selectively impaired learning when rats had to inhibit one strategy and shift to using a new strategy. However, comparable to orbitofrontal cortex inactivation, strategy-switching deficits following prelimbic inactivation resulted from a perseverance of the previously relevant strategy. Fewer studies have examined the infralimbic region, but there is some evidence suggesting that this region supports reversal learning by maintaining the reliable execution of a new choice pattern. Dorsomedial striatal inactivation impaired both reversal learning and strategy switching. The behavioral flexibility deficits following dorsomedial striatal inactivation resulted from the inability to maintain a new choice pattern once selected. Taken together, the results suggest that orbitofrontal and prelimbic subregions differentially contribute to behavioral flexibility, but they are both critical for the initial inhibition of a previously learned strategy, while the dorsomedial striatum plays a broader role in behavioral flexibility and supports a process that allows the reliable execution of a new strategy once selected.

The Contribution of the Medial Prefrontal Cortex, Orbitofrontal Cortex, and Dorsomedial Striatum to Behavioral Flexibility

Several lines of evidence indicate that a modest increase in circulating glucose levels enhances memory. One mechanism underlying glucose effects on memory may be an increase in acetylcholine (ACh) release. The present experiment determined whether enhancement of spontaneous alternation performance by systemic glucose treatment is related to an increase in hippocampal ACh output. Samples of extracellular ACh were assessed at 12-min intervals using in vivo microdialysis with HPLC-EC. Twenty-four minutes after an intraperitoneal injection of saline or glucose (100, 250, or 1000 mg/kg), rats were tested in a four-arm cross maze for spontaneous alternation behavior combined with microdialysis collection. Glucose at 250 mg/kg, but not 100 or 1000 mg/kg, produced an increase in spontaneous alternation scores (69.5%) and ACh output (121.5% versus baseline) compared to alternation scores (44.7%) and ACh output (58.9% versus baseline) of saline controls. The glucose-induced increase in alternation scores and ACh output was not secondary to changes in locomotor activity. Saline and glucose (100-1000 mg/kg) treatment had no effect on hippocampal ACh output when rats remained in the holding chamber. These findings suggest that glucose may enhance memory by directly or indirectly increasing the release of ACh. The results also indicate that hippocampal ACh release is increased in rats performing a spatial task. Moreover, because glucose enhanced ACh output only during behavioral testing, circulating glucose may modulate ACh release only under conditions in which cholinergic cells are activated.

https://www.pnas.org/content/pnas/93/10/4693.full.pdf

Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose

These experiments examined the effects of dorsomedial striatal inactivation on the acquisition of a response and visual cue discrimination task, as well as a shift from a response to a visual cue discrimination, and vice versa. In Experiment 1, rats were tested on the response discrimination task followed by the visual cue discrimination task. In Experiment 2, the testing order was reversed. Infusions of 2% tetracaine did not impair acquisition of the response or visual cue discrimination but impaired performance when shifting from a response to a visual cue discrimination, and vice versa. Analysis of the errors revealed that the deficit was not due to perseveration of the previously learned strategy, but to an inability to maintain the new strategy. These results contrast with findings indicating that prelimbic inactivation impairs behavioral flexibility due to perseveration of a previously learned strategy. Thus, specific circuits in the prefrontal cortex and striatum may interact to enable behavioral flexibility, but each region may contribute to distinct processes that facilitate strategy switching.

http://depts.washington.edu/mizulab/Miz%20PDF%20pubs/Ragozzino%20M%20BNS%2002.pdf

Role of the dorsomedial striatum in behavioral flexibility for response and visual cue discrimination learning.

The present study examined whether inactivation of the prelimbic-infralimbic areas or the dorsal anterior cingulate area impairs strategy switching in the cheeseboard task. After implantation of a cannula aimed at either the prelimbic-infralimbic or dorsal anterior cingulate areas, all rats were tested in a spatial and a visual-cued version of the task. Some of the rats received the spatial version first, followed by the visual-cued version. The procedure for the other rats was reversed. Infusions of 2% tetracaine into the prelimbic-infralimbic or dorsal anterior cingulate areas did not impair acquisition of the spatial or visual-cued versions. However, inactivation of the prelimbic-infralimbic areas, but not the dorsal anterior cingulate area, impaired learning when rats were switched from one version to the other. These findings suggest that the prelimbic-infralimbic areas are involved in switching to new behavior-guiding strategies.

Michael E. Ragozzino

Papers

Involvement of the Prelimbic–Infralimbic Areas of the Rodent Prefrontal Cortex in Behavioral Flexibility for Place and Response Learning

The Contribution of the Medial Prefrontal Cortex, Orbitofrontal Cortex, and Dorsomedial Striatum to Behavioral Flexibility

Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose

Role of the dorsomedial striatum in behavioral flexibility for response and visual cue discrimination learning.

Involvement of rodent prefrontal cortex subregions in strategy switching.