Snyder lab poster presentations at the 2018 Society for Neuroscience meeting. Stop by and say hi!
Sat, Nov. 3 PM. 029.01 / A1 – Adult-born neurons are structurally plastic and remain morphologically distinct from developmentally-born neurons. *J. S. SNYDER, D. ESPINUEVA, T. O’LEARY, S. P. CAHILL, D. SEIB, J. D. COLE
While new neurons are continuously added postnatally in the dentate gyrus of the hippocampus, only a fraction survive to integrate into the existing neural circuitry. Hippocampal-dependent learning during modulates the survival and integration of adult-born neurons. However, little is known about learning-induced plasticity across stages of maturity, and whether developmentally-born neurons display experience-dependent plasticity. The present study therefore examined the effects of single-day intensive water maze training on dendritic, axonal, and spine morphology in rat retrovirally-labelled granule cells, birth-dated at either postnatal day 1, or in adulthood at 1, 3, or 6 weeks prior to testing. Learning had no effect on total dendritic length or total spine density. However, training did increase mushroom spine densities in 1 and 6-week-old adult-born cells. Spatial learning also altered spine distribution across the molecular layer; while adult-born cells displayed greater spine density in the outer two-thirds of the molecular layer, which receive inputs from the entorhinal cortex, learning reduced the regional disparity. Interestingly, 7-week-old adult-born cells were morphologically distinct from developmentally-born cells, displaying shorter dendritic length and greater spine densities. These differences could be due to immaturity of the adult-born cells or the fact that they were born in adulthood and not early postnatal development. To distinguish these possibilities, we injected retrovirus into adult rats and examined cells 8 and 24 weeks later. Here we find that the increased spine density in adult-born cells persists at 24 weeks of age. Moreover, 24-week-old adult-born cells having significantly more mushroom spines than younger adult-born cells and developmentally-born cells. Continued analyses of dendritic length and complexity, as well as presynaptic terminal frequency, size, and morphology will further our understanding of the plastic potential of granule cells across stages of maturity. Collectively, our data suggest that adult-born granule cells exhibit learning-induced plasticity at specific cell ages. Moreover, structural differences between developmentally-born cells old adult-born cells suggests that adult-born neurons either mature over much longer timescales than previously appreciated, or are a functionally distinct cell type from developmentally-born cells.
Sun, Nov. 4 AM. 162.08 / CCC1 – Neurogenesis impacts delay-based decision making and affects neuronal activity in the ventral hippocampus. *D. R. SEIB, D. ESPINUEVA, O. PRINCZ-LEBEL, E. CHAHLEY, S. B. FLORESCO, J. S. SNYDER.
Depression is a complex disorder with disruptions in motivation, decision making and valuing future rewards. One brain region that has been implicated in the pathology of depression is the hippocampus. Interestingly, in humans it is the brain region that is capable of generating new neurons throughout life. Our aim was to identify the impact of adult hippocampal neurogenesis on the valuation of future rewards since previous research did mainly look at very basic motivational depressive-like behaviors. Here, we used a rat model and operant conditioning allowing us to investigate a complex behavior that is affected in depression. In detail, we used hGFAP-TK (TK) rats to deplete actively dividing neural progenitors by administering the antiviral drug Valganciclovir (VGCV) and consequently stop the production of new neurons. We tested TK rats on a delay discounting paradigm, where animals must choose between a low immediate reward and a larger delayed reward. Compared to WT rats, TK rats showed a decreased preference for the high reward with increasing delay times, indicating that neurogenesis increases the subjective value of future rewards. We were able to replicate this by ablating neurogenesis with irradiation in WT rats. On the contrary, increasing neurogenesis by running led to increased preference for the delayed high reward. On the cellular level, we found that the expression of the activity induced immediate early gene zif268 (erg-1) was reduced in VGCV treated TK rats in the general neuron population of the dentate gyrus specifically in the ventral hippocampus after performing the delay discounting task. Additionally, we labelled new-born neurons with a retrovirus before animals were trained on the delay discounting paradigm, and found that learning this task increased the dendritic complexity of 3-month-old neurons in both, the ventral and the dorsal dentate gyrus compared to cells from animals that were trained in a version of the task without delays. This project uses a novel rat model to study the impact of neurogenesis on future thinking. In summary, we find that neurogenesis increases the preference for future rewards and lack of neurogenesis leads to a reduction in neuronal activity in the ventral dentate gyrus during task performance. Furthermore, learning this delay-based decision making task alters the integration of new born neurons into the dentate network by increasing their dendritic complexity. Our findings are important in understanding altered behaviors in neurological disorders, such as depression, addiction or Alzheimer’s Disease, where value of future rewards is decreased and neurogenesis has been implicated in the disease pathology.
Sun, Nov. 4 AM. 166.14 / GGG10 – Adult-born neurons inhibit developmentally-born neurons. *A. ASH, J. CLEMANS-GIBBON, T. P. O’LEARY, D. R. SEIB, E. CHAHLEY, J. S. SNYDER.
Recent reports indicate that lateral inhibition plays a powerful role in selecting which dentate gyrus (DG) neurons are recruited during memory formation. This raises the question of whether developmentally-born and adult-born DG neurons have distinct roles for inhibition, particularly in vivo when neuronal ensembles are selected during memory encoding. To address this we combined chemogenetics and immunohistochemistry for BrdU+Fos to silence and measure activity in developmentally and adult-born neurons as rats learned a spatial water maze task. Specifically, retrovirus was injected into the DG of male rats at 6 weeks of age to express the inhibitory DREADD receptor, HM4Di, in neurons born in adulthood. The same rats were also injected with BrdU to label developmentally or adult-born neurons. At 10 weeks of age rats were injected with either the HM4Di agonist CNO or vehicle, then trained in the water maze (8 trials). One hour after water maze training brains were collected and processed immunohistochemically for BrdU, GFP and c-Fos to identify neurons that were recruited during learning. We found that silencing a subset of adult-born neurons (aged 4 weeks) increased activity levels in the developmentally-born neuron population. However, silencing adult-born neurons did not affect activation in other adult-born neurons within the DG, suggesting limited interaction within the adult-born population. We are currently looking at activation of interneurons (PV+ and SST+) within each treatment group to determine if silencing adult born cells impacts downstream activity in inhibitory interneurons. Our findings indicate there is a modulatory subcircuit between cell populations of different ages within the DG, which has implications for the role of adult neurogenesis on neuron recruitment during learning.
Mon, Nov. 5 AM. 280.15 / C23 – Functional maturation of mossy fiber terminals from adult-generated hippocampal dentate granule cells. *N.P. Vyleta. D.R. Seib. J.S. Snyder.
The dentate gyrus of the hippocampus is one of few regions in the mammalian brain to exhibit continued neurogenesis throughout adulthood, and these neurons may be uniquely suited to contribute to information transfer through hippocampal circuits. Understanding the mechanisms of how these new neurons signal in the mature network—both receiving inputs and transmitting output signals—is fundamentally important to understanding their roles in hippocampal function. It is well established that adult-generated granule neurons experience a period of enhanced excitability of the somato-dendritic compartment, as well as greater plasticity at the input synapses coming from the entorhinal cortex (Schmidt-Hieber et al., 2004; Ge et al., 2007). However, the time course of the development of output synapses from these neurons into the CA3 region of the hippocampus remains far less clear. Because the shape and dynamics of the action potential waveform at a presynaptic bouton determines calcium entry and ultimately the efficacy of release of neurotransmitter (Geiger and Jonas, 2000), how the electrical impulse at output mossy fiber terminals from adult-generated granule neurons develops with cell age could have important time-dependent effects on synaptic plasticity. Here, we have systematically characterized electrical properties of output mossy fiber terminals from adult-generated granule neurons using direct patch clamp recordings (Geiger and Jonas, 2000; Vyleta and Jonas, 2014). Recordings were made at various time points after induction of a fluorescent reporter in granule neurons in Ascl1CreERT2;CAGfloxstopTom mice. Neurons were labeled during adulthood (6- to 8-weeks of animal age) and during early development (postnatal day 0-3). The size and kinetics of action potentials, dynamics of the action potential waveform during trains of stimuli, excitability threshold, input resistance and resting capacitance were evaluated as a function of cell age, and compared between adult-born and early development-born groups.