Jason Shumake

Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats.

BACKGROUND Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). METHODS The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. RESULTS Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. CONCLUSIONS Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.

Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior

Congenitally helpless rats have been selectively bred to display an immediate helpless response to stress in order to model hereditary brain differences that contribute to depression vulnerability. Differences in regional brain metabolism between congenitally helpless and non-helpless rats were investigated using quantitative cytochrome oxidase histochemistry. The results indicated that congenitally helpless rats had 64-71% elevated metabolism in the habenula and a 25% elevation in the related interpeduncular nucleus. In contrast, helpless rats had 28% reduced metabolism in the ventral tegmental area (VTA) and 14-16% reductions in the basal ganglia and basolateral and central amygdala. The opposite metabolic changes in the habenula and ventral tegmental area may be especially important for determining the congenitally helpless rats global pattern of brain activity, which resembles the metabolic activity pattern produced by dopamine antagonism.

Brain Systems Underlying Susceptibility to Helplessness and Depression

There has been a relative lack of research into the neurobiological predispositions that confer vulnerability to depression. This article reviews functional brain mappings from a genetic animal model, the congenitally helpless rat, which is predisposed to develop learned helplessness. Neurometabolic findings from this model are integrated with the neuroscientific literature from other animal models of depression as well as depressed humans. Changes in four major brain systems are suggested to underlie susceptibility to helplessness and possibly depression: (a) an unbalanced prefrontal-cingulate cortical system, (b) a dissociated hypothalamic-pituitary-adrenal axis, (c) a dissociated septal-hippocampal system, and (d) a hypoactive brain reward system, as exemplified by a hypermetabolic habenula-interpeduncular nucleus pathway and a hypometabolic ventral tegmental area-striatum pathway. Functional interconnections and causal relationships among these systems are considered and further experiments are suggested, with theoretical attention to how an abnormality in any one system could affect the others.

Chronic administration of 13-cis-retinoic acid increases depression-related behavior in mice

Retinoid signaling plays a well-established role in neuronal differentiation, neurite outgrowth, and the patterning of the anteroposterior axis of the developing neural tube. However, there is increasing evidence that nutritional vitamin A status and retinoid signaling play an important role in the function of the adult brain. 13-Cis-retinoic acid (13-cis-RA) (isotretinoin or Accutane), a synthetic retinoid that is an effective oral treatment for severe nodular acne, has been linked with depression and suicide in patients. The purpose of this study was to test the hypothesis that chronic administration of 13-cis-RA would lead to depression-related behaviors in mice. Young, adult male mice received 13-cis-RA (1 mg/kg) by daily intraperitoneal injection for 6 weeks. This treatment paradigm produced plasma levels of 13-cis-RA that are comparable to those reported in human patients taking Accutane. In both the forced swim test and the tail suspension test, we found that 13-cis-RA-treated mice spent significantly more time immobile compared to vehicle-treated controls. In the open field test, there was no change in anxiety-related behavior in 13-cis-RA-treated mice. Furthermore, chronic administration of 13-cis-RA did not impair locomotion in either the open field or the rotarod test. Taken together, these results suggest that administration of 13-cis-RA increases depression-related behaviors in mice.

Effects of maternal separation, early handling, and standard facility rearing on orienting and impulsive behavior of adolescent rats

Effects of maternal separation in rats have been extensively investigated, but no studies have examined its effects in rat adolescence. We examined the effects of neonatal infant-mother separation (MS) for 6h/day and early handling (EH) for 10 days during the first 2 weeks of life by comparing MS and EH groups to standard facility reared (SFR) controls. At adolescence, the animals were evaluated in a novel and familiar open-field, the light-dark box, and the sucrose consumption test. Behavioral indices included orienting behavior (rearing frequency and duration), impulsive behavior (movement velocity and risk taking by entering the center of the open field or the light compartment of the light-dark box), hyperactivity (ambulatory distance and stereotypic movement), and reward-seeking behavior (sucrose drinking time). The prolonged MS during the first 2 weeks of life resulted in decreased orienting behavior and increased impulsive behavior in adolescence. Measures of ambulatory and stereotypic movements showed that MS rats were hyperactive in the novel environment whereas EH rats were less active overall. The impulsive/hyperactive phenotype produced by this MS protocol may provide a useful animal model to investigate the neurological basis for the similar behavioral phenotype found in attention deficit/hyperactivity disorder.

Differential Neuromodulation of Acquisition and Retrieval of Avoidance Learning by the Lateral Habenula and Ventral Tegmental Area

Several studies suggest an opponent functional relationship between the lateral habenula (LHb) and the ventral tegmental area (VTA). Previous work has linked LHb activation to the inhibition of dopaminergic neurons during loss of reward, as well as to deficits in escape and avoidance learning. We hypothesized that a dopamine signal might underlie the negative reinforcement of avoidance responses and that LHb activation could block this signal and thereby cause avoidance deficits. To test this idea, we implanted stimulating electrodes in either the VTA or LHb of gerbils engaged in two-way active avoidance learning, a task that shows learning-associated dopamine changes and that is acquired faster following LHb lesions. We delivered brief electrical brain stimulation whenever the animal performed a correct response, i.e., when the successful avoidance of foot shock was hypothesized to trigger an intrinsic reward signal. During the acquisition phase, VTA stimulation improved avoidance performance, while LHb stimulation impaired it. VTA stimulation appeared to improve both acquisition and asymptotic performance of the avoidance response, as VTA-stimulated animals reached above-normal performance but reverted to normal responding when stimulation was discontinued. The effects of LHb stimulation during avoidance acquisition were long lasting and persisted even after stimulation was discontinued. However, when given after successful acquisition of avoidance behavior, LHb stimulation had no effect, indicating that LHb stimulation specifically impaired avoidance acquisition without affecting memory retrieval or motivation or ability to perform the avoidance response. These results demonstrate opponent roles of LHb and VTA during acquisition but not during retrieval of avoidance learning.

Congenital helpless rats as a genetic model for cortex metabolism in depression

The validity of congenital helplessness as a genetic rat model for human depression was investigated in cortical regions of the rat brain thought to be analogous to those showing abnormalities in human neuroimaging studies. Cortex metabolism was analyzed using quantitative cytochrome oxidase histochemistry. Congenital helpless rats showed changes in frontal and cingulate regions comparable to those that have demonstrated metabolic differences in human depression. Significant metabolic decreases were found in dorsal frontal, medial orbital, and anterior cingulate, whereas a significant increase was found in infraradiata (subgenual) cingulate. The direction of these changes were the same as those seen in human studies. These findings support the validity of congenital helplessness as a model for human depression.

Brain differences in newborn rats predisposed to helpless and depressive behavior

Inborn brain differences in metabolic capacity were mapped in congenitally helpless rats, a genetically selected strain predisposed to show helpless and depressive behavior. There are a number of brain regions showing abnormal metabolism in adult congenitally helpless rats. Some of these alterations may be innate while others may be due to environmental factors, such as maternal care and postnatal stress. To identify which brain structures show innate differences, brains of newborn rats from congenitally helpless and non-helpless strains were compared using cytochrome oxidase histochemistry, an endogenous marker of regional metabolic capacity. A smaller subset of regions affected in adults showed significantly less metabolic activity in the newborn brains, including paraventricular hypothalamus, habenula, hippocampus, subiculum, lateral septal nucleus, anterior cingulate cortex, infralimbic cortex, and medial orbitofrontal cortex. A covariance analysis further revealed a striking reduction of functional connectivity in the congenitally helpless brain, including a complete decoupling of limbic forebrain regions from midbrain/diencephalic regions. This pattern of brain metabolism suggests that helplessness vulnerability is linked to altered functioning of limbic networks that are key to controlling the hypothalamic-pituitary-adrenal axis. This implies that vulnerable animals have innate deficits in brain systems that would normally allow them to cope with stress, predisposing them in this manner to more readily develop helpless and depressive behaviors.

DISSOCIATION OF SEPTO-HIPPOCAMPAL METABOLISM IN THE CONGENITALLY HELPLESS RAT

Congenitally helpless rats, selectively bred to model features of endogenous depression, appear to have a paraventricular hypothalamic nucleus (PVH) that is markedly hyperactive. This study investigated septal and hippocampal regions purported to regulate the PVH. We found that cytochrome oxidase, an index of oxidative metabolism and neural activity, was significantly elevated in the hippocampus and subiculum of congenitally helpless rats. However, reduced activity was observed in the lateral and medial septal nuclei, the nucleus of the diagonal band, and the bed nucleus of the stria terminalis. This dissociation between hippocampal and septal activity may be a predisposing factor for the development of helpless behavior.

Hypermetabolism of paraventricular hypothalamus in the congenitally helpless rat

The congenitally helpless rat, selectively bred to model behavioral features of depression, has shown metabolic activity patterns in frontal and cingulate cortex similar to those detected in human imaging studies of depression and sadness. This study extends the same metabolic mapping technique (quantitative cytochrome oxidase histochemistry) to the hypothalamus, where activity levels were assessed in six nuclei: paraventricular nucleus, medial preoptic area, lateral hypothalamic area, supraoptic nucleus, suprachiasmatic nucleus, and ventromedial nucleus. Helpless rats were compared with a strain of non-helpless rats selectively bred for stress resistance. Only the paraventricular nucleus showed a significant group difference, with helpless rats showing elevated metabolism and non-helpless rats showing reduced metabolism relative to normal rats. Thus, paraventricular nucleus activity may be associated with genetic susceptibility to helpless behavior.