Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

SUMMARY Granulocyte colony stimulating factor (G-CSF) is a multi-modal hematopoietic growth factor, which also has profound effects on the diseased central nervous system. G-CSF has been shown to enhance recovery from neurologic deficits in rodent models of ischemia. G-CSF appears to facilitate neuroplastic changes by both mobilization of bone marrow-derived cells and by its direct actions on CNS cells. The overall objective of the study was to determine if G-CSF administration in a mouse model of AD (Tg APP/PS1) would impact hippocampal-dependent learning by modifying the underlying disease pathology. A course of sub-cutaneous administration of G-CSF for a period of less than three weeks significantly improved cognitive performance, decreased β-amyloid deposition in hippocampus and entorhinal cortex and augmented total microglial activity. Additionally, G-CSF reduced systemic inflammation indicated by suppression of the production or activity of major pro-inflammatory cytokines in plasma. Improved cognition in AD mice was associated with increased synaptophysin immunostaining in hippocamal CA1 and CA3 regions and augmented neurogenesis, evidenced by increased numbers of calretinin-expressing cells in dentate gyrus. Given that G-CSF is already utilized clinically to safely stimulate hematopoietic stem cell production, these basic research findings will be readily translated into clinical trials to reverse or forestall the progression of dementia in AD.

Rodents exposed to environmental enrichment show many differences, including improved cognitive performance, when compared to those living in standard (impoverished) housing. The purpose of the present study was to determine if a selective increase in neurogenesis occurred in cognitivelyprotected Tg mice raised in an enriched environment compared to those reared in physical activity housing. At weaning, double Tg APP+PS1 mice were placed into one of three environments: complete environmental enrichment (CE), enhanced physical activity (PA), or individual, impoverished housing (IMP). At 9-10 months of age, Tg mice were injected with BrdU (100 mg/kg BID) followed by euthanasia either 24 hrs or two weeks after the last injection. Unbiased estimates of BrdU positive cells in the hippocampal subgranular zone revealed a significant increase in cellular proliferation in Tg mice raised in CE or PA compared to Tg mice reared in IMP housing. However, counts of BrdU birth-dated cells two weeks after labeling showed no difference among the three groups, indicating decreased survival of cells in those groups (CE and PA) with higher cellular proliferation rates in the neurogenic niche. Counts of calretinin-expressing cells, a marker of immature neurons, also indicated no difference among the three groups of mice. In view of our prior study showing that enhanced cognitive activity (but not enhanced physical activity) protects Tg mice against cognitive impairment, the present results indicate that increased generation and survival of new neurons in the hippocampal dentate gyrus is not involved with the cognitively-protective effects of complete CE in Alzheimer's transgenic mice.

Initiation and experimentation with illicit drugs often occurs in adolescence. Evidence suggests that adolescent rats are more sensitive to some of the effects of drugs of abuse than adult rats. The present study investigated whether adolescent and adult female Sprague Dawley rats differ in cocaine-induced locomotor activity. Animals were placed in the test environment for 30 minutes, and then administered an intraperitoneal (IP) injection of either cocaine (20mg/kg) or saline (0.9%). Both adult and adolescent animals showed significant increases in locomotor activity as a result of cocaine administration compared to saline controls. Interestingly, cocaine induced significantly more locomotor activity in the adolescent females compared to the adults, demonstrating that cocaine acts differently in developing animals.

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Following their birth in the adult hippocampal dentate gyrus, newborn progenitor cells migrate into the granule cell layer where they differentiate, mature, and functionally integrate into existing circuitry. The hypothesis that adult hippocampal neurogenesis is physiologically important has gained traction, but the precise role of new-born neurons in hippocampal function remains unclear. We investigated whether loss of new neurons impacts dendrite morphology and glutamate levels in area CA3 of the hippocampus by utilizing a human GFAP promoter-driven thymidine kinase genetic mouse model to conditionally suppress adult neurogenesis. We found that chronic ablation of new neurons induces remodeling in CA3 pyramidal cells and increases stress-induced release of the neurotransmitter glutamate. The ability of persistent impairment of adult neurogenesis to influence hippocampal dendrite morphology and excitatory amino acid neurotransmission has important implications for elucidating newborn neuron function, and in particular, understanding the role of these cells in stress-related excitoxicity.

The use of cocaine during adolescent development could alter the normal growth of brain regions affected by cocaine, specifically the reward system, and impact the adult mesolimbic system. However, there is scant literature aimed at determining whether animals are more vulnerable to the adverse effects of drugs during adolescence. The present study investigated whether cocaine pretreatment in either adolescence or adulthood altered the dopaminergic response to a naturally reinforcing substance in adulthood. To evaluate the responsivity of the mesolimbic system after repeated cocaine, sucrose was offered during the dialysis procedure and dialysates were collected. Regardless of age all saline pretreated rats had significant increases in sucrose-induced extracellular dopamine (DA) levels in the nucleus accumbens septi (NAcc) as compared to baseline levels. Rats pretreated with cocaine as adults also had significant increases in DA levels after sucrose. Interestingly, sucrose intake significantly enhanced DA levels in cocaine pretreated adolescent rats as compared to all other conditions. The results from the present study show that in rats pretreated with cocaine during adolescence there is an enhanced response of the dopaminergic system in animals exposed to a naturally reinforcing substance. Therefore, cocaine exposure during adolescence results in long-term functional changes in the mesolimbic pathway. Future studies need to ascertain the underlying mechanisms and their potential role in cocaine addiction.

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