Post-stress glucose consumption facilitates hormesis and resilience to severe stress.

Oral ingestion of a glucose solution following severe stress is a simple and effective way of preventing several of the negative sequelae of stress in rats. Similar resilience is obtained through hormetic training - pre-exposure to mild-to-moderate stress prior to severe stress. Here, we examined whether hormetic training is facilitated when a glucose solution is available following each hormetic training session. In Experiment 1, all rats were pre-exposed to a 30 min hormetic session of 25 inescapable tailshocks on each of 3 days. The schedule or hormesis differed between groups. The hormetic sessions occurred on either 3 consecutive days or with an interpolated day of rest between each hormetic session. Furthermore, in each of these conditions, one group had access to water and one group had access to a 40% glucose solution immediately after each hormetic session to complete a 2x2 factorial design. All groups were exposed to 100 inescapable tailshocks on the day following the end of hormetic training. Shuttle-escape testing occurred 24 h later. In Experiment 2, rats received two consecutive days of 100 inescapable tailshocks. Water or glucose was available following each session. Testing occurred 24 h after the second shock exposure. Experiment 1 replicated previous findings that rats exposed to hormetic training with interpolated rest did not show exaggerated fear responding or shuttle-escape deficits that normally result from 100 inescapable tailshocks, but training was ineffective if no rest was given between stress sessions. However, all post-stress glucose groups showed an elimination of helpless behavior. In Experiment 2, it was revealed that even 100 tailshocks can be made hormetic by post-stress glucose consumption.

Rigid patterns of effortful choice behavior after acute stress in rats.

Physical effort is a common cost of acquiring rewards, and decreased effort is a feature of many neuropsychiatric disorders. Stress affects performance on several tests of cognition and decision making in both humans and nonhumans. Only a few recent reports show impairing effects of stress in operant tasks involving effort and cognitive flexibility. Brain regions affected by stress, such as the medial prefrontal cortex and amygdala, are also implicated in mediating effortful choices. Here, we assessed effort-based decision making after an acute stress procedure known to induce persistent impairment in shuttle escape and elevated plasma corticosterone. In these animals, we also probed levels of polysialyted neural cell adhesion molecule (PSA-NCAM), a marker of structural plasticity, in medial frontal cortex and amygdala. We found that animals that consistently worked for high magnitude rewards continued to do so, even after acute shock stress. We also found that PSA-NCAM was increased in both regions after effortful choice experience but not after shock stress alone. These findings are discussed with reference to the existing broad literature on cognitive effects of stress and in the context of how acute stress may bias effortful decisions to a rigid pattern of responding.

Isolation of the differential effects of chronic and acute stress in a manner that is not confounded by stress severity.

Firm conclusions regarding the differential effects of the maladaptive consequences of acute versus chronic stress on the etiology and symptomatology of stress disorders await a model that isolates chronicity as a variable for studying the differential effects of acute versus chronic stress. This is because most previous studies have confounded chronicity with the total amount of stress. Here, we have modified the stress-enhanced fear learning (SEFL) protocol, which models some aspects of posttraumatic stress disorder (PTSD) following an acute stressor, to create a chronic variant that does not have this confound. Comparing results from this new protocol to the acute protocol, we found that chronic stress further potentiates enhanced fear-learning beyond the nonassociative enhancement induced by acute stress. This additional component is not observed when the unconditional stimulus (US) used during subsequent fear learning is distinct from the US used as the stressor, and is enhanced when glucose is administered following stressor exposure, suggesting that it is associative in nature. Furthermore, extinction of stressor-context fear blocks this additional associative component of SEFL as well as reinstatement of generalized fear, suggesting reinstatement of generalized fear may underlie this additional SEFL component.

Dissociable consequences of moderate and high volume stress are mediated by the differential energetic demands of stress.

Exposure to traumatic stress leads to persistent, deleterious behavioral and biological changes in both human and non-human species. The effects of stress are not always consistent, however, as exposure to different stressors often leads to heterogeneous effects. The intensity of the stressor may be a key factor in determining the consequences of stress. While it is difficult to quantify intensity for many stress types, electric shock exposure provides us with a stressor that has quantifiable parameters (presentation length x intensity x number = shock volume). Therefore, to test the procedural differences in shock volume that may account for some reported heterogeneity, we used two common shock procedures. Learned helplessness is a commonly reported behavioral outcome, highlighted by a deficit in subsequent shuttle-box escape, which requires a relatively high-volume stress (HVS) of about 100 uncontrollable shocks. Conversely, stress-enhanced fear learning (SEFL) is another common behavioral outcome that requires a relatively moderate-volume stress (MVS) of only 15 shocks. We exposed rats to HVS, MVS, or no stress (NS) and examined the effects on subsequent fear learning and normal weight gain. We found doubly dissociable effects of the two levels of stress. MVS enhanced contextual fear learning but did not impact weight, while HVS produced the opposite pattern. In other words, more stress does not simply lead to greater impairment. We then tested the hypothesis that the different stress-induced sequalae arouse from an energetic challenge imposed on the hippocampus by HVS but not MVS. HVS rats that consumed a glucose solution did exhibit SEFL. Furthermore, rats exposed to MVS and glucoprivated during single-trial context conditioning did not exhibit SEFL. Consistent with the hypothesis that the inability of HVS to enhance fear learning is because of an impact on the hippocampus, HVS did enhance hippocampus-independent auditory fear learning. Finally, we provide evidence that stressors of different volumes produce dissociable changes in glutamate receptor proteins in the basolateral amygdala (BLA) and dorsal hippocampus (DH). The data indicate that while the intensity of stress is a critical determinant of stress-induced phenotypes that effect is nonlinear.

Dissociation in Effective Treatment and Behavioral Phenotype Between Stress-Enhanced Fear Learning and Learned Helplessness.

Post-traumatic stress disorder (PTSD) is a debilitating disease with relatively high lifetime prevalence. It is marked by a high diversity of symptoms and comorbidity with other psychiatric disease. Furthermore, PTSD has a high level of origin and symptom heterogeneity within the population. These characteristics taken together make it one of the most challenging diseases to effectively model in animals. However, with relatively little headway made in developing effective disease interventions, PTSD remains as a high priority target for animal model study. Learned Helplessness (LH) is a procedure classically used to model depression, but has in recent years transitioned to use as a model of PTSD. Animals in this procedure receive 100 inescapable and unpredictable tailshocks or simple restraint without shock. The following day, the animals are tested in a shuttle box, where inescapably-shocked subjects exhibit exaggerated fear and profound deficit in escape performance. Stress-enhanced fear learning (SEFL) also uses an acute (single session) stressor for modeling PTSD in rodents. The SEFL procedure begins with exposure to 15 footshocks or simple context exposure without shock. Animals that initially received the 15 footshocks exhibit future enhanced fear learning. In this review, we will compare the behavior, physiology, and interventions of these two animal models of PTSD. Despite considerable similarity (a single session containing inescapable and uncontrollable shock) the two procedures produce a very divergent set of behavioral consequences.

Post-Stress Fructose and Glucose Ingestion Exhibit Dissociable Behavioral and Physiological Effects.

An acute traumatic event can lead to lifelong changes in stress susceptibility and result in psychiatric disease such as Post-Traumatic Stress Disorder (PTSD). We have previously shown that access to a concentrated glucose solution for 24 hours beginning immediately after trauma decreased stress-related pathology in the learned helplessness model of PTSD and comorbid major depression. The current study sought to investigate the peripheral physiological effects of post-stress glucose consumption. We exposed 128 male Sprague-Dawley rats to inescapable and unpredictable 1-milliamp electric tail shocks or simple restraint in the learned helplessness procedure. Rats in each stress condition had access to a 40% glucose solution, 40% fructose solution, or water. Blood and liver tissue were extracted and processed for assay. We assessed corticosterone, corticosteroid-binding globulin (CBG), glucose, and liver glycogen concentrations at various time points following stress. We found that rats given access to glucose following exposure to traumatic shock showed a transient rise in blood glucose and an increase in liver glycogen repletion compared to those that received water or fructose following exposure to electric shock. We also found that animals given glucose following shock exhibited reduced free corticosterone and increased CBG compared to their water-drinking counterparts. However, this difference was not apparent when glucose was compared to fructose. These data suggest that post-stress glucose prophylaxis is likely not working via modulation of the HPA axis, but rather may provide its benefit by mitigating the metabolic challenges of trauma exposure.