Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus

Abstract

Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.long-term potentiation ͉ learning ͉ memory N ew neurons are born in the dentate gyrus (DG) of the hippocampus throughout the life of mammals (1) and derive from dividing progenitor cells located in the innermost part of the granule cell layer, a region called the subgranular zone. Young granule neurons integrate into the existing circuitry of the hippocampus, as evidenced by the development of functional synaptic inputs provided by the medial perforant path (MPP) and growth of axons to target cells in CA3 (2). Although a variety of environmental and pharmacological manipulations can affect neurogenesis (2, 3), it is unclear whether adult-born neurons provide a significant contribution to hippocampal function and, ultimately, how it might impact behavior.Recent studies have shown that various strategies to disrupt neurogenesis produce a limited impairment in some hippocampaldependent learning and memory tasks and in responses to antidepressant drugs (4-11). Unfortunately, the lack of spatial and cellular specificity provided by most ablation techniques has made it difficult to ascertain whether the consequent behavioral effects were caused by ablation of neurogenesis or other impairments. To circumvent these problems we have used two independent strategies of ablation. The first is a previously reported x-ray procedure that differs from similar methods in two ways: (i) the x-ray administration is restricted to a fraction of the brain containing the hippocampus and spares neurogenesis in the neighboring subventricular zone; and (ii) mice are allowed to recover for 3 months before testing to allow for the disappearance of markers of inflammation, such as reactive microglia (9). The second method of ablation is a genetic strategy that directly targets dividing progenitors throughout the brain and avoids potential radi...

Intrahippocampal Transplantation of Transgenic Neural Precursor Cells Overexpressing Interleukin-1 Receptor Antagonist Blocks Chronic Isolation-Induced Impairment in Memory and Neurogenesis

“…Chronic social isolation also exacerbated the effect of another chronic stressor (daily foot-shock for 3 weeks) on the production of new hippocampal neurons (Westenbroek et al, 2004), and precluded the positive influence of short-term running on neurogenesis (Stranahan et al, 2006). Our findings are consistent with these reports, demonstrating that chronic isolation decreased the production of new neurons, which has been implicated in some hippocampal-dependent learning and memory tasks (Shors et al, 2001;Shors, 2004;Saxe et al, 2006). Thus, it can be suggested that chronic isolation-induced reduction in neurogenesis may be involved in the memory impairment in contextual fear conditioning and spatial memory that accompanies this condition.…”

“…Furthermore, exposure to acute psychological stressors, such as short-term (3-5 h) isolation, increased hippocampal IL-1 levels and produced memory impairments that were completely blocked by an intrahippocampal injection of IL-1ra (Barrientos et al, 2003(Barrientos et al, , 2004. Stressful conditions, such as social isolation, also influence several aspects of neural plasticity, including hippocampal neurogenesis (Dong et al, 2004;Westenbroek et al, 2004;Stranahan et al, 2006), which is critically important for some hippocampal-dependent learning and memory tasks (Shors et al, 2001(Shors et al, , 2002Saxe et al, 2006;Winocur et al, 2006). We have recently demonstrated that chronic mild stress, as well as chronic administration of IL-1b, markedly reduces hippocampal neurogenesis .…”

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

“…While the Morris water maze task is not influenced by antimitotic treatment 35,43 , newly generated neurons are activated following this task at a higher rate, relative to mature neurons 44 . Similar distinctions have been reported with respect to the role of adult-generated neurons in recognition memory; enhancement of performance on the novel object preference task following environmental enrichment was reversed by systemic treatment with an antimitotic 45 , but spontaneous alternation in the Y-maze, which also involves recognition memory, was unaffected following focal cranial irradiation 35 . Although it remains to be determined whether adult-generated granule neurons make a meaningful contribution to performance on these tasks under baseline conditions, the therapeutically relevant question is whether new neurons can enhance performance following neurodegeneration or injury.…”

“…No studies to date have reported an effect of diabetes on learning-induced changes in hippocampal glucose Lowering corticosterone levels in diabetes can restore behavioral function on tasks that recruit both new and mature neurons. While the Morris water maze task is not influenced by antimitotic treatment 35,43 , newly generated neurons are activated following this task at a higher rate, relative to mature neurons 44 . Similar distinctions have been reported with respect to the role of adult-generated neurons in recognition memory; enhancement of performance on the novel object preference task following environmental enrichment was reversed by systemic treatment with an antimitotic 45 , but spontaneous alternation in the Y-maze, which also involves recognition memory, was unaffected following focal cranial irradiation 35 .…”

“…(c), Sham-operated db/db mice exhibit reduced dentate gyrus LTP, but db/db mice with normal physiological levels of corticosterone are not impaired. (d), Insulinresistant mice that had been sham-operated also exhibit impaired LTP in the presence of picrotoxin, which decreases local inhibition and also blocks GABAergic excitation on new neurons 34,35 . In contrast, insulin-resistant mice with normal physiological levels of corticosterone show control levels of LTP under these conditions.…”