Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.

Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. 56Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as 28Si, influences hippocampal neurogenesis and function. To compare the influence of 28Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body 28Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/µ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67+, BrdU+, BrdU+NeuN+ and DCX+ cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67+, BrdU+ and DCX+ cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67+ and DCX+ cells in 0.2 Gy group relative to control group and fewer BrdU+ and DCX+ cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU+ cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU+ cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU+ cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy 28Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body 28Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that 28Si-radiation exposure damag...

Prefrontal cortical executive functions comprise a number of cognitive capabilities necessary for goal directed behavior and adaptation to a changing environment. Executive dysfunction that leads to maladaptive behavior and is a symptom of psychiatric pathology can be instigated or exacerbated by stress. In this review we survey research addressing the impact of stress on executive function, with specific focus on working memory, attention, response inhibition, and cognitive flexibility. We then consider the neurochemical pathways underlying these cognitive capabilities and, where known, how stress alters them. Finally, we review work exploring potential pharmacological and non-pharmacological approaches that can ameliorate deficits in executive function. Both preclinical and clinical literature indicates that chronic stress negatively affects executive function. Although some of the circuitry and neurochemical processes underlying executive function have been characterized, a great deal is still unknown regarding how stress affects these processes. Additional work focusing on this question is needed in order to make progress on developing interventions that ameliorate executive dysfunction.

Deficits in cognitive flexibility, the ability to modify behavior in response to changes in the environment, contribute to the onset and maintenance of stress-related neuropsychiatric illnesses, such as depression. Cognitive flexibility depends on medial prefrontal cortex (mPFC) function, and in depressed patients, cognitive inflexibility is associated with hypoactivity and decreased glutamate receptor expression in the mPFC. Rats exposed to chronic unpredictable stress (CUS) exhibit compromised mPFC function on the extradimensional (ED) set-shifting task of the attentional set-shifting test. Moreover, CUS-induced ED deficits are associated with dendritic atrophy and decreased glutamate receptor expression in the mPFC. This evidence suggests that impaired glutamate signaling may underlie stress-induced deficits in cognitive flexibility. To test this hypothesis, we first demonstrated that blocking NMDA or AMPA receptors in the mPFC during ED replicated CUS-induced deficits in naïve rats. Secondly, we found that expression of activity-regulated cytoskeleton-associated protein (Arc) mRNA, a marker of behaviorally induced glutamate-mediated plasticity, was increased in the mPFC following ED. We then showed that CUS compromised excitatory afferent activation of the mPFC following pharmacological stimulation of the mediodorsal thalamus (MDT), indicated by a reduced induction of c-fos expression. Subsequently, in vivo recordings of evoked potentials in the mPFC indicated that CUS impaired afferent activation of the mPFC evoked by MDT stimulation, but not the ventral hippocampus. Lastly, glutamate microdialysis, showed that CUS attenuated the acute stress-evoked increase in extracellular glutamate in the mPFC. Together, these results demonstrate that CUS-induced ED deficits are associated with compromised glutamate neurotransmission in the mPFC.

Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), is a widely used herbal medicine. Ginsenosides, the active ingredients of ginseng, are the main components responsible for many beneficial actions of ginseng. In the present study, we tested ten different ginsenosides in the previously developed in vitro Huntington's disease (HD) assay with primary medium spiny striatal neuronal cultures (MSN) from the YAC128 HD mouse model. We found that nanomolar concentrations of ginsenoside Rb1 and Rc effectively protected YAC128 medium spiny neurons from glutamate-induced apoptosis; and that Rg5 was protective at micromolar concentration. The other seven ginsenosides tested were not effective or exerted toxic effects in MSN cultures. In further experiments we suggested that neuroprotective effects of ginsenosides Rb1, Rc, and Rg5 could correlate with their ability to inhibit glutamate-induced Ca 2+ responses in cultured MSN. From these results we concluded that ginsenosides Rb1, Rc and Rg5 offer a potential therapeutic choice for the treatment of HD and possibly other neurodegenerative disorders.

Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse.

Chronic stress compromises cognition, including executive function mediated in the medial prefrontal cortex (mPFC). To investigate mechanisms underlying these processes, we use chronic unpredictable stress (CUS), which reduces activity in the mPFC and impairs cognitive set-shifting, a measure of cognitive flexibility in laboratory rats. It has been shown that CUS attenuates the local electrical field potential response evoked in the mPFC by stimulation of the ascending excitatory afferent from the mediodorsal thalamus (MDT). Thus, in this study, to investigate the role that such changes in afferent-evoked responsivity of the mPFC might play in the cognitive deficits induced by CUS, we used optogenetics to directly induce plastic changes in the thalamic-mPFC afferent pathway. Glutamatergic neurons in the MDT were virally-induced to express the ChETA variant of channelrhodopsin. Then, to first validate the optogenetic induction of plasticity, long-term depression (LTD) or long-term potentiation (LTP) were induced by laser stimulation of ChETA-expressing terminals in the mPFC of anesthetized rats. In subsequent experiments, induction of opto-LTD in awake animals produced set-shifting deficits similar to those induced by CUS. By contrast, inducing opto-LTP in rats that had received prior CUS treatment corrected the stress-induced deficit in set-shifting. These results suggest that stress-induced plasticity in the thalamic-mPFC pathway is sufficient to produce stress-induced cognitive deficits, and may represent a novel target for effective therapeutic intervention to correct cognitive impairment in stress-related psychiatric disorders.

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