Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats

Abstract

New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Wnt-1 KO Altered central and peripheral neuronal development during initial axonogenesis [54] Wnt-1 KO Impaired midbrain development [55] Wnt-1 dominant negative Impaired hippocampal neurogenesis and spatial and object recognition memory [56,57] Wnt-1 overexpression Reduced neural differentiation of mESCs (also by treatment with lithium chloride) [58] Wnt-1 KO Increased differentiation into DA neurons in KO mESCs [59] Wnt-2 KO Decreased progenitor proliferation and neurogenesis in the ventral midbrain [60] Wnt-2 overexpression Induced dendritic arborization in hippocampal progenitors [61] Wnt-3 overexpression Increased differentiation of cortical intermediate [43] progenitors Wnt-3 overexpression Induced differentiation through cleavage of RYK in cortical progenitors [62] Wnt-3a KO Loss of the hippocampus [42] Recombinant Wnt-3a Induced GABAergic neuronal differentiation through RYK, reduced oligodendrogenesis [63] Recombinant Wnt-3a Induced differentiation of hESCs [64] Recombinant/purified Wnt-3a…”

“…Further evidence that Wnt-mediated neurogenesis contributes to adult hippocampal function comes from studies in which lentiviral expression of a dominant-negative form of Wnt-1 (dnWnt-1) was found to reduce neurogenesis, resulting in impaired long-term retention of spatial and object recognition memory [56,57].…”

A morphologically distinct granule cell type in the dentate gyrus of the red fox correlates with adult hippocampal neurogenesis

“…Red foxes have also been shown to be more curious and exploratory than other carnivores kept in zoos (Kusak and Huber, 1991), however, when living within cities, they remain shy and alert towards humans. In rodents, explorative behavior in elevated plus maze does not correlate with neurogenesis (Shors et al, 2002), but the level of neurogenesis correlates with the behavioral pattern in an open field test (Naylor et al, 2008), and object recognition (Bruel-Jungerman et al, 2005;Jessberger et al, 2009). …”

Object/context-specific memory deficits associated with loss of hippocampal granule cells after adrenalectomy in rats

“…Despite the short retention, the behavior of ADX rats was impaired specifically in the object/context mismatch task. Prior research has demonstrated that larger disruptions of DG function can also impair novel object preference (Lee et al 2005;Jessberger et al 2009) and spatial behavior (Sutherland et al 1983;Xavier et al 1999;Gilbert et al 2001). A possible explanation for this disparity is that discriminations based upon context may typically require a higher degree of complexity in information load, resulting in a greater sensitivity to DG granule cell layer disruption.…”