Iris Gispan

Elucidation of the neurobiology of depression: insights from a novel genetic animal model.

Development of drugs for the effective treatment of depressive disorders requires elucidation of factors that are critical for clinically antidepressant effects. During the past 4 years, we have studied in situ neurochemical alterations in the brain that may underlie depressive behavior. This was achieved using the genetically-selected Flinders Sensitive Line (FSL) of rats (a unique animal model of depression), before and after chronic antidepressant treatment. This line of rats exhibits behavioral features characteristic of depression, and responds to chronic, but not acute, antidepressant treatments. This review summarizes our findings concerning the local neuro-dynamics in the brain during manifestation of depressive behavior and effective antidepressant treatment in this animal model of depression. Understanding the abnormalities manifested in neurochemical pathways during depressive disorders and the dynamic effects of these abnormalities on the onset of action and efficacy of pharmacological treatments are crucial for the development of effective antidepresssant drugs and therapeutic strategies.

Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior

Adult bone marrow-derived mesenchymal stem cells (MSCs) are regarded as potential candidates for treatment of neurodegenerative disorders, because of their ability to promote neurogenesis. MSCs promote neurogenesis by differentiating into neural lineages as well as by expressing neurotrophic factors that enhance the survival and differentiation of neural progenitor cells. Depression has been associated with impaired neurogenesis in the hippocampus and dentate gyrus. Therefore, the aim of this study was to analyze the therapeutic potential of MSCs in the Flinders sensitive line (FSL), a rat animal model for depression. Rats received an intracerebroventricular injection of culture-expanded and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled bone marrow-derived MSCs (105 cells). MSC-transplanted FSL rats showed significant improvement in their behavioral performance, as measured by the forced swim test and the dominant–submissive relationship (DSR) paradigm. After transplantation, MSCs migrated mainly to the ipsilateral dentate gyrus, CA1 and CA3 regions of the hippocampus, and to a lesser extent to the thalamus, hypothalamus, cortex and contralateral hippocampus. Neurogenesis was increased in the ipsilateral dentate gyrus and hippocampus of engrafted rats (granular cell layer) and was correlated with MSC engraftment and behavioral performance. We therefore postulate that MSCs may serve as a novel modality for treating depressive disorders.

High cocaine dosage decreases neurogenesis in the hippocampus and impairs working memory.

Drug addiction is a chronic brain disorder, characterized by the loss of the ability to control drug consumption. The neurobiology of addiction is traditionally thought to involve the mesocorticolimbic system of the brain. However, the hippocampus has received renewed interest for its potential role in addiction. Part of this attention is because of the fact that drugs of abuse are potent negative regulators of neurogenesis in the adult hippocampus and may as a result impair learning and memory. We investigated the effects of different dosages of contingent cocaine on cell proliferation and neurogenesis in the dentate gyrus of the hippocampus and on working memory during abstinence, using the water T‐maze test, in adult rats. We found that cocaine, in addition to the changes it produces in the reward system, if taken in high doses, can attenuate the production and development of new neurons in the hippocampus, and reduce working memory.

Nanoparticle-based CT imaging technique for longitudinal and quantitative stem cell tracking within the brain: application in neuropsychiatric disorders.

A critical problem in the development and implementation of stem cell-based therapy is the lack of reliable, noninvasive means to image and trace the cells post-transplantation and evaluate their biodistribution, final fate, and functionality. In this study, we developed a gold nanoparticle-based CT imaging technique for longitudinal mesenchymal stem cell (MSC) tracking within the brain. We applied this technique for noninvasive monitoring of MSCs transplanted in a rat model for depression. Our research reveals that cell therapy is a potential approach for treating neuropsychiatric disorders. Our results, which demonstrate that cell migration could be detected as early as 24 h and up to one month post-transplantation, revealed that MSCs specifically navigated and homed to distinct depression-related brain regions. We further developed a noninvasive quantitative CT ruler, which can be used to determine the number of cells residing in a specific brain region, without tissue destruction or animal scarification. This technique may have a transformative effect on cellular therapy, both for basic research and clinical applications.

The role of dehydroepiandrosterone (DHEA) in drug-seeking behavior

Conventional substance-abuse treatments have only had limited success especially for drugs such as cocaine, methamphetamine and nicotine. Newer data have begun to shed light on the complexity of the addictive process and new treatment approaches, including interference with brain neurosteroids, to attenuate drug-seeking behavior, are in advanced stages of development. Neurosteroids are synthesized in the brain and peripheral tissues, from cholesterol or steroidal precursors imported from peripheral sources. The most abundant neurosteroids in the human body are DHEA and its sulfate ester, DHEAS. These neurosteroids can act as modulators of neurotransmitter receptors, such as γ-aminobutyric-acid-type A (GABA(A)), NMDA, and sigma-1 receptors which may contribute to apparent enduring behavioral manifestations facilitated by substances of abuse. Neurosteroid concentrations respond to environmental and behavioral circumstances, such as stress and mood, both which are involved in the progression of substance use that advance substance addiction. This article reviews the current literature pertaining to neurosteroids and substances of abuse, focusing on DHEA, and discusses its role in drug-seeking behavior as suggested by preclinical observations.

Preloads of corn oil inhibit independent ingestion on postnatal day 15 in rats.

The ontogenetic development of postingestive inhibitory control of ingestion by an oil preload was examined in preweaning rats. Gastric preloads (5% b.wt) of water, mineral oil or corn oil were administered 5 min before a 30-min intake test in which pups licked milk from the floor of a test chamber. Preloads of corn oil decreased intake significantly compared with preloads of mineral oil or water on Postnatal Days 15 and 18, but not on Postnatal Day 12. Because preloads of corn oil reduced intake ore than preloads of mineral oil, it is possible that the inhibitory effect of corn oil is due to its fats rather than to its oily texture. Cholecystokinin (CCK), presumably released from the small intestine, apparently mediates part of this inhibitory effect because pretreatment with devazepide, a specific CKKA antagonist, significantly reduced the inhibition produced by corn oil.

Postingestive inhibitory controls of independent ingestion in 12-day-old rats

The postingestive inhibitory control of independent ingestion produced by gastric preloads was investigated in 12-day-old Sprague-Dawley rats. Pups received isovolumetric (5% of body weight) preloads of saline (0.9%), glucose (5%, 10%, or 20%) or maltose (5%, 10%, or 20%) 5 min before a 30-min independent ingestion test in which pups licked milk from the floor of the test chamber. All preloads reduced intake significantly compared to the control condition in which pups were intubated, but no preload was administered. The reduction of intake produced by the isovolumetric, isotonic solutions (saline, 5% glucose, and 10% maltose) is consistent with the stimulation of a preabsorptive, inhibitory mechanism sensitive to volume. The significantly larger reduction of intake produced by isovolumetric, hypertonic solutions (20% glucose and 20% maltose) is consistent with the stimulation of an additional postingestive inhibitory mechanism sensitive to the osmotic, saccharidic, or, in the case of 20% glucose, metabolic properties of these solutions. Because preloads were given 5 min prior to the intake tests, it is likely that the site of action of both inhibitory mechanisms was preabsorptive, although a postabsorptive site for part of the inhibitory effect of 20% glucose cannot be excluded.

Lateral habenula deep brain stimulation for personalized treatment of drug addiction

Drug addiction is a major brain disease, and a serious clinical and social problem. The number of adults who require substance abuse treatment is anticipated to escalate from 1.7 million in 2000 and 2001 to 4.4 million in 2020 (Gfroerer et al., 2003). Addiction is a gradual process, which begins with occasional use, proceeds to regular use and finally progresses to uncontrollable abuse. The main problem is the high rates of relapse among abusers who have ceased drug use. Cocaine, in particular, is one of the most prevalent recreational drugs, with especially high relapse rates (Bossert et al., 2005). To date, there are no approved pharmacological treatments for stimulant drugs of abuse such as cocaine.

Characteristics of glucose and maltose preloads that inhibit feeding in 12-day-old rats

Nonvolumetric inhibitory control of food intake during independent ingestion was studied in rats on postnatal day 12. Pups received either sham intubation or equivolumetric (5% BW) preloads of 20% (w/v) glucose, 20% maltose, 20% 2-deoxy-D-glucose (2-DG), 0.9% NaCl, 200 mg soybean trypsin-inhibitor (SBTI) or distilled water, 5 min prior to 30-min access to a milk diet spread on the floor of a beaker. To investigate if endogenous cholecystokinin mediated any of the inhibitory effects of the preloads on intake, pups were injected IP with 1 mg/kg devazepide, a specific CCK(A) receptor antagonist, or with vehicle 30 min prior to the intake test. All preloads reduced intake (measured by percent body weight gain) compared to sham intubation. Glucose (20%) reduced intake significantly more than 0.9% saline, but not more than the preload of 20% 2-DG. This suggests that the effect of glucose can be accounted for by its preabsorptive osmotic properties because 2-DG is not actively transported or metabolized. The inhibitory effect of 20% maltose may also be due to its osmotic load, but these experiments did not provide clear evidence for this. Cholecystokinin apparently did not mediate the effect of any of the preloads except SBTI, because devazepide only reduced the inhibition produced by a preload of SBTI. These results provide further evidence that hypertonic stimuli in the stomach or small intestine provide inhibitory control of food intake by postnatal day 12.

A cholecystokinin receptor antagonist blocks milk-induced but not maternal-contact-induced decrease of ultrasonic vocalization in rat pups

The role of cholecystokinin (CCK) in reducing separation-induced ultrasonic vocalization (USV) was examined by peripheral administration (of the selective CCK(A) receptor antagonist devazepide to 10-11-day-old rats. Pups placed alone for 2 min emitted a mean of 55.1 USV/min. When placed on a paper towel wet with warm, sweet milk, USV rate decreased to 23.2/min for the following 8 min. Devazepide (150-600 microg/kg IP) prevented this USV reduction, but did not increase feeding. In contrast, USV reduction produced by contact with the anesthetized dam was not affected by devazepide. Similarly, the opiate antagonist naltrexone (0.5 and 1.0 mg/kg) has been shown to block morphine-induced USV decrease in pups away from the dam, but was ineffective when USV reduction was induced by the presence of the dam (Blass et al., 1990; Carden & Hofer, 1990). The current findings suggest that CCKs role is specific, in that it mediates milk- but not dam-induced quieting of USV. The results, however, are not incompatible with the possibility that CCK and opioids are part of multiple, redundant pathways that mediate the quieting of USV by the dam.