The Snyder lab, along with collaborators in the Psychology Department at UBC, will be presenting FIVE posters at SFN this year! Here they are, in order of how hard it was for me to find them on my hard drive, email etc.
EARLY SURVIVAL AND DELAYED DEATH OF DEVELOPMENTALLY-BORN DENTATE GYRUS NEURONS
Shaina Cahill, Ru Qi Yu, Evgenia Todorova, Dylan Green, Jason Snyder
Much effort has been spent trying to understand the function of adult-generated hippocampal neurons. At the cellular level, adult-generated neurons progress through defined developmental stages that are characterized by specific patterns of synapse formation, marker expression, physiological function and cell death. Less is known about the developmental timecourse of neurons born during the perinatal period. To address this question we injected rats with the mitotic marker BrdU at postnatal day 6, to label neurons born at the peak of dentate gyrus development. We then counted and characterized BrdU+ cells at 1hr, 1d, 3d, 1w, 2w, 3w, 4w and 8w timepoints. Unlike adult-born neurons, which undergo significant cell death during the first 4 weeks after mitosis, we observed no loss of developmentally-born cells after the 1w timepoint. Developmentally-born neurons upregulated NeuN and downregulated DCX comparably to what has been observed in adult-born neurons. To assess functional integration of BrdU+ neurons, we examined expression of the immediate-early genes c-fos and zif268 (rats explored a novel environment). Similar to what has been observed in adult-born neurons, there was an early peak in zif268 expression. However, peak zif268 expression occurred when neurons were 2w old, which is 1w earlier than adult-born cells and consistent with evidence that developmentally-born neurons mature faster than adult-born neurons. Exploration-induced c-fos expression was present in a smaller proportion of neurons, did not show an early peak, and plateaued at the 4w timepoint. To investigate whether developmentally-born neurons continue to survive throughout adulthood we injected additional groups of rats with BrdU at postnatal day 6 and quantified surviving BrdU+ cells at 2 months and 6 months. In contrast to the stable survival between 1w-8w, we observed a 17% loss of BrdU+ cells between 2-6months. Developmentally-born neurons expressed caspase3 when rats were 2 months old, providing additional evidence that these neurons underwent cell death. Collectively, our findings indicate that developmentally-born and adult-born neurons differ markedly in their patterns of survival: during stages of neuronal immaturity, adult-born neurons die but developmentally-born neurons are stable; when neurons have reached maturity, adult-born neurons are stable and developmentally-born neurons die. By identifying temporal patterns by which developmentally-born persist throughout the lifespan, these findings may be relevant for understanding the dynamic nature of hippocampal memory.
THE ROLE OF ADULT NEUROGENESIS IN VISUO-SPATIAL LEARNING AND MEMORY IS DEPENDENT ON STRESS DURING TRAINING AND SEX
Timothy P. O’Leary and Jason S. Snyder
Adult neurogenesis in the hippocampus is involved in visuo-spatial learning and memory, and also regulation of the hypothamic-pituitary-adrenal axis and stress-related behaviour. It is not yet clear, however, if the role of adult-born neurons in learning and memory is dependent on stress levels during the learning episode. To address this possibility, we used a transgenic rat that expresses the herpes simplex virus thymidine kinase, under the glial fibrillary acidic protein promoter (GFAP-TK). Administration of the anti-viral drug valganciclovir leads to death of mitotic neural precursor cells in the GFAP-TK rat. Beginning at 6 weeks of age, GFAP-TK rats were given valganciclovir orally for 6 weeks (twice per week), leading to a near-complete ablation of adult-neurogenesis in the dentate gyrus. To assess the role of adult-neurogenesis in learning and memory under stress, we tested GFAP-TK (N=96) and wild-type long-evans (N=103) rats in the Morris water maze using either cold 16°C water (high stress) or warm 25°C water (low to moderate stress). Rats completed acquisition training for 3 days (4 trials per day) with a probe trial (60 sec) on the following day to assess memory for the escape platform location. Both male and female rats were used, given that sex differences are found in behavioural responses to stress, and because few studies have examined sex differences in the role of adult-neurogenesis. When trained in 16°C water, sex-dependent effects on learning were found. In males, WT rats found the escape platform faster and travelled a shorter distance than GFAP-TK rats. The opposite result was found in females, as GFAP-TK rats located the escape platform faster and traveled a shorter distance than WT rats. These differences between genotypes were not found in 25°C water, and were not due to differences in swim-speed. In the probe trial, there was a trend for better memory performance in male WT rats than GFAP-TK rats, but only at the colder 16°C water. Overall sex differences in performance were found at 25°C but not 16°C, where male rats showed superior learning and memory, and slower swim speed compared to females. These results suggest that in males, adult neurogenesis is involved to a greater extent in visuo-spatial learning and memory during stressful learning episodes. The learning and memory performance of females, however, appears to be spared or even enhanced when neurogenesis is ablated. These results suggest a novel sex difference in the role of hippocampal adult-born neurons in visuo-spatial learning and memory, and underscore the importance of using both sexes when investigating the function of adult-born neurons.
ADULT NEUROGENESIS REGULATES DELAY-BASED DECISION MAKING
Jason Snyder, Ru Qi Yu, Delane Espinueva, Oren Princz-Lebel, Erin Chahley, Stan B Floresco, Desiree R Seib
Neural progenitors in the hippocampus generate new neurons throughout life. In several neurological disorders the production of new neurons is interrupted, for example in depression. Behavioral traits that are altered in depression include assigning less value to future outcomes, decreased motivation to obtain rewards and increased sensitivity towards negative feedback. Previous studies have investigated the effects of reduced neurogenesis on mood but the exact nature of these disturbances is unknown. To address this we have used a novel transgenic rat (GFAP-TK) in which neurogenesis can be specifically inhibited in adulthood, and operant decision-making tests of behaviors that are commonly disrupted in depression. We first tested rats on a delay-based decision-making task, where they must choose between a low reward lever that delivers 1 sugar pellet immediately and a high reward lever that delivers 4 pellets after a delay. Compared to intact wild types (WT), GFAP-TK rats showed a decreased preference for the high reward option with increasing delay times, indicating that adult neurogenesis increases the subjective value of future rewards. Second, we employed a probabilistic reversal learning task where rats have to show optimal behavior in the face of an uncertain reward. Here, correct (80% rewarded) and incorrect (20% rewarded) levers switch after 8 correct consecutive trials, and the number of reversals indicates behavioral flexibility. WT and GFAP-TK rats achieved a similar number of reversals. Moreover, win-stay and lose-shift behavior was also similar, indicating that neurogenesis does not regulate reward feedback sensitivity or negative feedback sensitivity, respectively. Third, we are performing an effort-based decision-making task where the number of lever presses required to receive the high reward option increases across blocks. Since depression is often associated with reduced energy and motivation, we may expect that neurogenesis-deficient GFAP-TK rats are less willing to choose the large reward option when additional work is required. This project combines a novel rat model with complex behavioral tasks to study the role of new neurons in decision-making behaviors that are disrupted in depression. Ongoing experiments will investigate the cellular mechanisms by which new neurons promote valuation of future rewards. Identifying these mechanisms may be helpful for developing treatments for depression and other disorders characterized by impulsivity and devaluation of future rewards, such as schizophrenia, Alzheimer’s disease and addiction.
DISRUPTION OF NEONATAL NEUROGENESIS PRODUCES COGNITIVE DEFICITS THAT ARE DISTINCT FROM THOSE OBSERVED IN SCHIZOPHRENIA
Maric T Tse, Patrick Piantadosi, Meagan Auger, Shaina Cahill, John-Darby Cole, Jason Snyder, Stan B Floresco
Disruption of neonatal neural development via neonatal ventral hippocampal lesion or impeding early neurogenesis has been proposed to underlie pathophysiology that leads to cognitive deficits associated in schizophrenia in adulthood. In the present study, we sought to assess whether disrupting neonatal neurogenesis in transgenic rats that express herpes simplex virus thymidine kinase (TK) under control of the glial fibrillary-associated protein (GFAP) promotor may alter behavior and cognition in adulthood. TK transgenics and wide-type controls were treated with the antiviral drug valganciclovir (Valg; 10-20mg/kg) or saline on post-natal day (PND) 5/7/9, and tested on a number of cognitive/behavioral assays at 2 months of age. Interestingly, unlike other types of neonatal manipulations, Valg treated TK rats did not show enhanced sensitivity to the psychomotor stimulant effects of amphetamine. However, neonatal treatment of Valg induced various degrees of motor deficits as revealed with tests of locomotion, and this was associated with reduced cerebellar volume. Valg treatment in TK transgenic rats resulted in severe spatial learning deficits on a delayed-response version of the radial arm maze, which is mediated by the hippocampus and medial prefrontal cortex. Subsequently, rats were tested on an operant version of strategy set-shift task that assesses cognitive flexibility. TK-Valg-treated rats showed severe impairment during learning of an the initial visual cue discrimination, but curiously, were unimpaired when they had to alter their strategy and use an egocentric response discrimination during set-shift. In a discriminative conditioned fear discrimination assay, TK-Valg-treated rats showed reduced fear to conditioned stimulus (CS) associated with foot-shock, and also showed more rapid extinction relative to all other groups. Lastly, tests of anxiety using the elevated plus maze revealed that TK-Valg-treated rats showed reduced time spent in open arms. Interestingly, TK transgenics treated with Valg showed reduction of head size (microcephaly). Collectively, it is suggested that disruption of neonatal neurogenesis at PND5/7/9 causes severe cognitive/learning deficits accompanied with motor dysfunction and cranial abnormalities, revealing effects that are qualitatively distinct than that of schizophrenia. This suggests that neurodevelopmental disruptions that causes schizophrenic-like phenotype require more targeted disruption of the development of hippocampal-prefrontal circuitry.
INHIBITION OF ADULT NEUROGENESIS IMPAIRS LEARNING OF SPATIOTEMPORAL REGULARITIES
Ru Qi Yu, Jiaying Zhao, Jason Snyder
The hippocampus is an important brain structure for learning in humans and other animals. Hippocampal neurogenesis is thought to play a critical role in pattern separation. Previous research has focused on the role of hippocampal neurogenesis in spatial learning, by training rodents to discriminate spatial contexts or locations. It is currently unknown what role hippocampal neurogenesis plays in the learning of regularities. Here, we examined how the inhibition of neurogenesis impacts learning of spatiotemporal regularities. Transgenic GFAP-TK rats were used whose hippocampal neurogenesis was inhibited selectively in adulthood by VGCV. The GFAP-TK rats were compared with intact wild-type littermates. Rats were trained in a spatial water maze task where they were required to find a hidden escape platform in a tank of opaque water. The platform appeared in one of two possible locations. The rats were randomly assigned to and remained in one of the three conditions throughout training: the platform appeared repeatedly in the same location for all trials on a given day (simple regularities condition), alternated between the two locations on a trial-by-trial basis (complex regularities condition), or randomly appeared between the two locations on a trial-by-trial basis (no regularities condition). The swim trajectory and the latency to reach the platform were recorded for each trial and compared between the GFAP-TK rats (lacking neurogenesis) and the wild type rats (with neurogenesis). We found that when the platform location alternated on each trial, the GFAP-TK rats performed reliably worse than wild type rats, both in terms of latency to reach the platform and swim trajectory. However, when the platform appeared repeatedly in the same location, or randomly appeared between locations, the GFAP-TK rats were not different from wild type rats. These results suggest that neurogenesis is critical for learning of complex but not simple spatiotemporal regularities.