A role for hippocampal adult neurogenesis in shifting attention toward novel stimuli

Weeden, Christy S. S.; Mercurio, Jeffrey; Cameron, Heather A.

doi:10.1016/j.bbr.2019.112152

Cited by 16 publications

(14 citation statements)

References 54 publications

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“…Improved behavioral performance has previously been observed in a radial arm maze task following irradiation to prevent adult neurogenesis (Saxe et al, 2007) and in Y maze and shuttle box tasks following hippocampal disruption (Gaffan, Bannerman, Warburton, & Aggleton, 2001; Isaacson, Douglas, & Moore, 1961). In one of these studies (Gaffan et al, 2001), enhanced attention to the key stimuli by animals with lesions appeared to be responsible for the improvement—an explanation that is consistent with decreased distractibility in runway and operant tasks observed following hippocampal lesions (Gustafson & Koenig, 1979; Raphelson, Isaacson, & Douglas, 1965) and decreased distractibility in TK rats in an orienting task (Weeden et al, 2019). A similar decrease in distraction by the mint odor stimulus likely explains the better maze performance observed in TK rats in the current study.…”

Section: Discussionmentioning

confidence: 84%

“…The 8‐week time point eliminates a substantial population of relatively mature and immature adult‐born neurons (Cole et al, 2020; Snyder et al, 2009; Snyder & Cameron, 2012), increasing the chances of seeing potential behavioral changes due to loss of adult neurogenesis relative to shorter time points. Behavioral effects on attention, sucrose‐preference, motivation, novelty‐suppressed feeding, and novel object‐location preference have been observed following 8 weeks of VGCV treatment (Cameron & Schoenfeld, 2018; Karlsson, Wang, Sonti, & Cameron, 2018; Snyder et al, 2016; Weeden, Mercurio, & Cameron, 2019). All procedures followed the Institute of Laboratory Animal Research guidelines and were approved by the NIMH Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

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Adult neurogenesis alters response to an aversive distractor in a labyrinth maze without affecting spatial learning or memory

et al. 2020

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Adult neurogenesis has been implicated in learning and memory of complex spatial environments. However, new neurons also play a role in nonmnemonic behavior, including the stress response and attention shifting. Many commonly used spatial tasks are very simple, and unsuitable for detecting neurogenesis effects, or are aversively motivated, making it difficult to dissociate effects on spatial learning and memory from effects on stress. We have therefore created a novel complex spatial environment, the flex maze, to enable reward-mediated testing of spatial learning in a flexibly configurable labyrinth. Using a pharmacogenetic method to completely inhibit neurogenesis in adulthood, we found that rats lacking new neurons (TK rats) and wild type controls completed and remembered most mazes equally well. However, control rats were slower to complete peppermint-scented mazes than other mazes, while neurogenesis-deficient rats showed no effect of mint on maze behavior, completing these mazes significantly faster than control rats. Additional testing found that wild type and TK rats showed similar detection of, avoidance of, and glucocorticoid response to the mint odor. These results suggest that spatial learning and memory in a labyrinth task is unaffected by the loss of new neurons, but that these cells affect the ability of an aversive stimulus to distract rats from completing the maze.

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Section: Discussionmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Adult neurogenesis alters response to an aversive distractor in a labyrinth maze without affecting spatial learning or memory

et al. 2020

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“…Our results indicate that different sedatives can affect different phases of neurogenesis. Inhibiting cell proliferation and increasing cell death both have the same net effect of decreasing the number of functional new neurons, possibly resulting in cognitive or emotional impairment (Cameron and Glover, 2017;Karlsson et al, 2018;Weeden et al, 2019). However, behavioral impairments resulting from these two effects would likely be observed at different time points after sedation; effects on nearly-mature neurons should have almost immediate consequences, while changes in proliferation would impact behavior only after a delay of several weeks.…”

Section: Resultsmentioning

confidence: 99%

“…BrdU was administered to all animals 28 days prior to anesthesia exposure to label adult-born neurons that are likely to be mature enough to be integrated into functional neural circuits and able to affect behavior (Snyder et al, 2009b;Gonçalves et al, 2016;Weeden et al, 2019), though new neurons continue to mature morphologically for several more weeks (John et al, 2020). Treatment with propofol showed a sex by treatment interaction, in which propofol decreased BrdU+ cell counts in female rats (by 34%) but not in male rats (Table 1 and Figure 4B).…”

Section: Propofol Reduces the Number Of Mature Neurons In The Dg Of Fmentioning

confidence: 99%

The Effects of Anesthesia on Adult Hippocampal Neurogenesis

2020

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In animal studies, prolonged sedation with general anesthetics has resulted in cognitive impairments that can last for days to weeks after exposure. One mechanism by which anesthesia may impair cognition is by decreasing adult hippocampal neurogenesis. Several studies have seen a reduction in cell survival after anesthesia in rodents with most studies focusing on two particularly vulnerable age windows: the neonatal period and old age. However, the extent to which sedation affects neurogenesis in young adults remains unclear. Adult neurogenesis in the dentate gyrus (DG) was analyzed in male and female rats 24 h after a 4-h period of sedation with isoflurane, propofol, midazolam, or dexmedetomidine. Three different cell populations were quantified: cells that were 1 week or 1 month old, labeled with the permanent birthdate markers EdU or BrdU, respectively, and precursor cells, identified by their expression of the endogenous dividing cell marker proliferating cell nuclear antigen (PCNA) at the time of sacrifice. Midazolam and dexmedetomidine reduced cell proliferation in the adult DG in both sexes but had no effect on postmitotic cells. Propofol reduced the number of relatively mature, 28-day old, neurons specifically in female rats and had no effects on younger cells. Isoflurane had no detectable effects on any of the cell populations examined. These findings show no general effect of sedation on adult-born neurons but demonstrate that certain sedatives do have drug-specific and sex-specific effects. The impacts observed on different cell populations predict that any cognitive effects of these sedatives would likely occur at different times, with propofol producing a rapid but short-lived impairment and midazolam and dexmedetomidine altering cognition after a several week delay. Taken together, these studies lend support to the hypothesis that decreased neurogenesis in the young adult DG may mediate the effects of sedation on cognitive function.

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“…For instance, hippocampal adult neurogenesis that occurs in the dentate gyrus has been found to be important in pattern discrimination and episodic memory, depression, and anxiety and attention (Gross, 2000). Moreover, these neurons are also suggested to be critical drivers of cognitive flexibility (Anacker and Hen, 2017;Weeden et al, 2019) and inhibition of NMDARs or GluN2B activity specifically has been shown to promote adult hippocampal neurogenesis and spatial memory retraining (Cameron et al, 1995;Gruden et al, 2018). Furthermore, spinophilin has been shown to interact with doublecortin (Dcx), a microtubule-associated protein, which in known to bundle microtubules in the growth cone and also is a marker of newly born neurons (Friocourt et al, 2003;Tsukada et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Spinophilin limits GluN2B-containing NMDAR activity and sequelae associated with excessive hippocampal NMDAR function

Salek

Bansal

Berbari

et al. 2021

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N-methyl-D-Aspartate receptors (NMDARs) are calcium-permeable ion channels that are ubiquitously expressed within the glutamatergic postsynaptic density. Phosphorylation of NMDAR subunits defines receptor activity and surface localization. Modulation of NMDAR phosphorylation by kinases and phosphatases regulates calcium entering the cell and subsequent activation of calcium-dependent processes. Spinophilin is the major synaptic protein phosphatase 1 (PP1) targeting protein that controls phosphorylation of myriad substrates via targeting or inhibition of PP1. Spinophilin limits NMDAR function in a PP1-dependent manner and we have previously shown that spinophilin sequesters PP1 away from the GluN2B subunit of the NMDAR, which results in increased phosphorylation of Ser-1284. However, how spinophilin modifies NMDAR function is unclear. Herein, we detail that while Ser-1284 phosphorylation increases calcium influx via GluN2B-containing NMDARs, overexpression of spinophilin decreases GluN2B-containing NMDAR activity by decreasing its surface expression. In hippocampal neurons isolated from spinophilin knockout animals there is an increase in cleaved caspase-3 levels compared to wildtype mice; however, this effect is not exclusively due to NMDAR activation; suggesting multiple putative mechanisms by which spinophilin may modulate caspase cleavage. Behaviorally, our data suggest that spinophilin knockout mice have deficits in spatial cognitive flexibility, a behavior associated GluN2B function within the hippocampus. Taken together, our data demonstrate a unique mechanism by which spinophilin modulates GluN2B containing NMDAR phosphorylation, channel function, and trafficking and that loss of spinophilin promotes pathological sequelae associated with GluN2B dysfunction.HIGHLIGHTSSpinophilin bidirectionally regulates GluN2B-containing NMDAR function.Loss of spinophilin in primary hippocampal neurons increases a pro-apoptotic marker.Loss of spinophilin in vivo decreases measures of spatial cognitive flexibility.Graphical AbstractSpinophilin increases the phosphorylation of Ser-1284 on GluN2B, thereby enhancing calcium influx through the GluN2B containing NMDARs. In contrast, spinophilin limits GluN2B-containing surface expression putatively due to modulation of GluN2B interactions with endocytotic proteins. Since the second effect of spinophilin occurs independent of the first, we observe an overall decrease in calcium influx through GluN2B containing NMDARs when spinophilin is present. This low, basal calcium influx is less likely to be promote calcium-dependent activation of caspase and downstream apoptotic pathways and permits flexible search strategies and behaviors. In the absence of spinophilin, the spinophilin-driven internalization of the receptors is decreased, more receptors are expressed on the surface and calcium influx into the cell is increased. This high levels of intracellular calcium triggers apoptotic pathways leading to cell death. This impact may be more dramatic in cells with high expression of GluN2B-containing NMDA receptors. This loss of spinophilin reduces cognitive flexibility in hippocampal dependent tasks.

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A role for hippocampal adult neurogenesis in shifting attention toward novel stimuli

Cited by 16 publications

References 54 publications

Adult neurogenesis alters response to an aversive distractor in a labyrinth maze without affecting spatial learning or memory

Adult neurogenesis alters response to an aversive distractor in a labyrinth maze without affecting spatial learning or memory

The Effects of Anesthesia on Adult Hippocampal Neurogenesis

Spinophilin limits GluN2B-containing NMDAR activity and sequelae associated with excessive hippocampal NMDAR function

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