Prenatal ethanol exposure enhances NMDAR-dependent long-term potentiation in the adolescent female dentate gyrus.

The dentate gyrus (DG) is a region of the hippocampus intimately involved with learning and memory. Prenatal exposure to either stress or ethanol can reduce long-term potentiation (LTP) in the male hippocampus but there is little information on how these prenatal events affect LTP in the adolescent female hippocampus. Previous studies suggest that deleterious effects of PNEE can, in part, be mediated by corticosterone, suggesting that prenatal stress might further enhance any alterations to LTP induced PNEE. When animals were exposed to a combination of prenatal stress and PNEE distinct sex differences emerged. Exposure to ethanol throughout gestation significantly reduced DG LTP in adolescent males but enhanced LTP in adolescent females. Combined exposure to stress and ethanol in utero reduced the ethanol-induced enhancement of LTP in females. On the other hand, exposure to stress and ethanol in utero did not alter the ethanol-induced reduction of LTP in males. These results indicate that prenatal ethanol and prenatal stress produce sex-specific alterations in synaptic plasticity in the adolescent hippocampus.

Characterization of the neurogenesis quiescent zone in the rodent brain: effects of age and exercise.

Although it is accepted that new neurons continue to be generated in the hippocampal dentate gyrus (DG) throughout adulthood, it has recently become apparent that this process is not homogeneous, and that a small region of the DG lacks neurogenesis. Here, we show that the relative area of this neurogenesis quiescent zone (NQZ) did not vary after the peak in hippocampal postnatal neurogenesis and until animals reached adulthood, although the ratio between its actual volume and the total volume of the DG doubled during this time. However, we were able to identify a few mitotic cells that reside within this subregion in early adolescent rats. Furthermore, these cells can be activated, and 1 week of voluntary exercise was enough to significantly increase the number of mitotic cells within the NQZ of adolescent rats. There was, however, no corresponding increase in the number of new neurons in this subregion of the DG, suggesting that some factor necessary to allow these cells to develop into a mature phenotype is missing. Moreover, the same intervention was ineffective in increasing either proliferation or neurogenesis in older adult rats. Surprisingly, we found no evidence for the existence of an NQZ in the mouse DG, suggesting that the neurogenic process in these two rodent species is differently regulated. Understanding the molecular mechanisms underlying the existence of the NQZ in the rat DG might shed light on the processes that regulate adult neurogenesis and its modulation by factors such as aging and exercise.

Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus.

Voluntary exercise and endogenous cannabinoid activity have independently been shown to regulate hippocampal plasticity. The aim of the current study was to determine whether the endocannabinoid system is regulated by voluntary exercise and if these changes contribute to exercise-induced enhancement of cell proliferation. In Experiment 1, 8 days of free access to a running wheel increased the agonist binding site density of the cannabinoid CB(1) receptor; CB(1) receptor-mediated GTPgammaS binding; and the tissue content of the endocannabinoid anandamide in the hippocampus but not in the prefrontal cortex. In Experiment 2, the CB(1) receptor antagonist AM251 (1 mg kg(-1)) was administered daily to animals given free access to a running wheel for 8 days, after which cell proliferation in the hippocampus was examined through immunohistochemical analysis of the cell cycle protein Ki-67. Voluntary exercise increased proliferation of progenitor cells, as evidenced by the increase in the number of Ki-67 positive cells in the granule cell layer of the dentate gyrus (DG) in the hippocampus. However, this effect was abrogated by concurrent treatment with AM251, indicating that the increase in endocannabinoid signaling in the hippocampus is required for the exercise-induced increase in cell proliferation. These data demonstrate that the endocannabinoid system in the hippocampus is sensitive to environmental change and suggest that it is a mediator of experience-induced plasticity.

NGF is essential for hippocampal plasticity and learning.

Nerve growth factor (NGF) is produced in the hippocampus throughout life and is retrogradely trafficked to septal cholinergic neurons, providing a potential mechanism for modulating cholinergic inputs and, thereby, hippocampal plasticity. To explore NGF modulation of hippocampal plasticity and function, NGF levels were augmented or blocked in intact adult rats, and subsequent in vivo effects on cholinergic neurons, hippocampal long-term potentiation (LTP), and learning were examined. NGF augmentation significantly enhanced cholinergic neuronal markers and facilitated induction of hippocampal LTP. Blockade of endogenous NGF significantly reduced hippocampal LTP and impaired retention of spatial memory. These findings reveal an essential role for NGF in regulating biological mechanisms related to plasticity and memory in the intact adult brain.

Exercising our brains: how physical activity impacts synaptic plasticity in the dentate gyrus.

Exercise that engages the cardiovascular system has a myriad of effects on the body; however, we usually do not give much consideration to the benefits it may have for our minds. An increasing body of evidence suggests that exercise can have some remarkable effects on the brain. In this article, we will introduce how exercise can impact the capacity for neurons in the brain to communicate with one another. To properly convey this information, we will first briefly introduce the field of synaptic plasticity and then examine how the introduction of exercise to the experimental setting can actually alter the basic properties of synaptic plasticity in the brain. Next, we will examine some of the candidate physiological processes that might underlay these alterations. Finally, we will close by noting that, taken together, this data points toward our brains being dynamic systems that are in a continual state of flux and that physical exercise may help us to maximize the performance of both our body and our minds.

Long-term depression in vivo: effects of sex, stress, diet, and prenatal ethanol exposure.

Long-term depression (LTD) of synaptic efficacy has proven a difficult phenomenon to examine in vivo, despite the ease with which it is induced in a variety of in vitro preparations. Prior exposure to an acute stressful episode does however seem to enhance the capacity of the hippocampus to exhibit LTD in vivo in male animals. In the present experiments, we examined the capacity for low-frequency stimuli (low-frequency stimulation (LFS)) to induce LTD in juvenile male and female animals following an acute stress episode. Interestingly, prior exposure to stress was only required for the induction of LTD in male animals, while both control and stressed female animals exhibited equivalent LTD. In animals that were exposed to ethanol in utero, a similar requirement for prior exposure to stress to elicit LTD was found for male, but not female animals. This prenatal ethanol exposure did not in itself alter the capacity for LTD induction in either sex; however, in utero food restriction did enhance LTD induction in both male and female animals, irrespective of whether they were exposed to stress just prior to being administered LFS. These results indicate that in utero dietary restriction more drastically affects CA1 LTD than in utero ethanol exposure. In addition, female animals seem to exhibit LTD in vivo in the absence of stress much more easily than their male counterparts.

Effects of exercise on NMDA receptor subunit contributions to bidirectional synaptic plasticity in the mouse dentate gyrus.

We examined synaptic plasticity in the dentate gyrus (DG) of the hippocampus in vitro in juvenile C57Bl6 mice (28-40 days of age), housed in control conditions with minimal enrichment (Controls) or with access to an exercise wheel (Runners). LTP expression was significantly greater in slices from Runners than in those from Controls, but could be blocked by APV in both groups. LTP was significantly reduced by NR2B subunit antagonists in both groups. NVP-AAM077, an antagonist with a higher preference for NR2A subunits over NR2B subunits, blocked LTP in slices from Runners and produced a slight depression in Control animals. LTD in the DG was also blocked by APV, but not by either of the NR2B specific antagonists. Strikingly, NVP-AAM077 prevented LTD in Runners, but not in Control animals, suggesting an increased involvement of NR2A subunits in LTD in animals that exercise. NVP-AAM077 did not block LTD in NR2A Knock Out (KO) animals that exercised, as expected. In an attempt to discern whether NMDA receptors located at extrasynaptic sites could play a role in the induction of LTD, DL-TBOA was used to block excitatory amino acid transport and increase extracellular glutamate levels. Under these conditions, LTD was not blocked by the co-application of a specific NR2B subunit antagonist in either group, but NVP-AAM077 again blocked LTD selectively in Runners. These results indicate that NR2A and NR2B subunits play a significant role in LTP in the DG, and that exercise can significantly alter the contribution of NMDA NR2A subunits to LTD.

Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment.

Acute stress impairs memory retrieval and facilitates the induction of long-term depression (LTD) in the hippocampal CA1 region of the adult rodent brain. However, whether such alterations in synaptic plasticity cause the behavioral effects of stress is not known. Here, we report that two selective inhibitors of the induction or expression of stress-enabled, N-methyl-D-aspartate receptor-dependent hippocampal LTD also block spatial memory retrieval impairments caused by acute stress. Additionally, we demonstrate that facilitating the induction of hippocampal LTD in vivo by blockade of glutamate transport mimics the behavioral effects of acute stress by impairing spatial memory retrieval. Thus, the present study demonstrates that hippocampal LTD is both necessary and sufficient to cause acute stress-induced impairment of spatial memory retrieval and provides a new perspective from which to consider the nature of cognitive deficits in disorders whose symptoms are aggravated by stress.

Tyrosine phosphorylation of the GluR2 subunit is required for long-term depression of synaptic efficacy in young animals in vivo.

The study of the intracellular mechanics that underlay changes in synaptic efficacy is a rapidly evolving field of research. It is currently believed that NMDA receptors play a significant role in the induction of synaptic plasticity, whereas AMPA receptors play a significant role in its expression. For AMPA receptors, it has been shown that tyrosine phosphorylation of the GluR2 carboxyl termini is required for the expression of long-term depression of synaptic efficacy (LTD) in vitro (Ahmadian et al. (2004) EMBO J 23:1040-1050). In the present study, we sought to determine whether similar mechanisms are involved in vivo, where different stimulation parameters are required for the induction of LTD. We initially used a paired-burst (PB) paradigm that reliably induces LTD in vivo. In these animals we were able to prevent the induction and expression of PB-LTD by administering a peptide (GluR-3Y) that acted as a competitive inhibitor of tyrosine phosphorylation. In a separate set of animals, we exposed animals to brief periods of stress (S) before using low-frequency stimuli to induce LTD (S-LTD). Again, GluR2-3Y blocked both the induction and expression of S-LTD. In contrast, an inert version of the peptide, with alanine replacing the three tyrosine residues, did not inhibit LTD induction. In addition, we demonstrated that GluR2-3Y did not affect the induction of long-term potentiation in vivo. These findings support the hypothesis that tyrosine phosphorylation and AMPA receptor endocytosis are necessary steps for the induction and maintenance of two forms of LTD in the CA1 region.