J. Martin Wojtowicz

Mice Lacking Metabotropic Glutamate Receptor 5 Show Impaired Learning and Reduced CA1 Long-Term Potentiation (LTP) But Normal CA3 LTP

Class I metabotropic glutamate receptors (mGluRs) have been postulated to play a role in synaptic plasticity. To test the involvement of one member of this class, we have recently generated mutant mice that express no mGluR5 but normal levels of other glutamate receptors. The CNS revealed normal development of gross anatomical features. To examine synaptic functions we measured evoked field EPSPs in the hippocampal slice. Measures of presynaptic function, such as paired pulse facilitation in mutant CA1 neurons, were normal. The response of mutant CA1 neurons to low concentrations of (1S,3R)−1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) was missing, which suggests that mGluR5 may be the primary high affinity ACPD receptor in these neurons. Long-term potentiation (LTP) in mGluR5 mutants was significantly reduced in the NMDA receptor (NMDAR)-dependent pathways such as the CA1 region and dentate gyrus of the hippocampus, whereas LTP remained intact in the mossy fiber synapses on the CA3 region, an NMDAR-independent pathway. Some of the difference in CA1 LTP could lie at the level of expression, because the reduction of LTP in the mutants was no longer observed 20 min after tetanus in the presence of 2-amino-5-phosphonopentanoate. We propose that mGluR5 plays a key regulatory role in NMDAR-dependent LTP. These mutant mice were also impaired in the acquisition and use of spatial information in both the Morris water maze and contextual information in the fear-conditioning test. This is consistent with the hypothesis that LTP in the CA1 region may underlie spatial learning and memory.

Heterogenous properties of dentate granule neurons in the adult rat

Postnatal neurogenesis contributes substantially to the neuronal population of the adult dentate gyrus. We report here that the neurons located in the deep aspects of the granule cell layer, near the proliferative zone, have different properties from those located in the superficial layers. The former group of neurons, tentatively designated as young, can be readily identified in a standard hippocampal slice preparation by morphological, immunohistochemical, and electrophysiological criteria. Electrophysiological recordings and imaging with Lucifer yellow from these neurons in the standard hippocampal slice preparation showed one or two main dendrites and conically shaped branches possessing varicose protrusions. These features are in agreement with the appearance of the same population of young neurons immunopositive for TOAD-64, a marker for immature neurons. In disinhibited slices, these putative young neurons are distinguished from the mature neurons, located in the superficial granule cell layer, by showing paired pulse facilitation and having a lower threshold for induction of long-term potentiation. The putative young neurons are completely unaffected by GABA(A) inhibition and always display robust long-term potentiation. In contrast, the mature neurons never produce long-term potentiation when the GABA(A) inhibition is intact. We propose that the heterogeneity of the functional properties of the granule neurons is related to the ongoing neurogenesis in the adult animals.

Neurogenesis in the Dentate Gyrus of the Rat Following Electroconvulsive Shock Seizures

Electroconvulsive shock (ECS) seizures provide an animal model of electroconvulsive therapy (ECT) in humans. Recent evidence indicates that repeated ECS seizures can induce long-term structural and functional changes in the brain, similar to those found in other seizure models. We have examined the effects of ECS on neurogenesis in the dentate gyrus of the adult rat using bromodeoxyuridine (BrdU) immunohistochemistry, which identifies newly generated cells. Cells have also been labeled for neuronal nuclear protein (NeuN) to identify neurons. One month following eight ECS seizures, ECS-treated rats had approximately twice as many BrdU-positive cells as sham-treated controls. Eighty-eight percent of newly generated cells colabeled with NeuN in ECS-treated subjects, compared to 83% in sham-treated controls. These data suggest that there is a net increase in neurogenesis within the hippocampal dentate gyrus following ECS treatment. Similar increases have been reported following kindling and kainic acid- or pilocarpine-induced status epilepticus. Increased neurogenesis appears to be a general response to seizure activity and may play a role in the therapeutic effects of ECT.

A model of hippocampal neurogenesis in memory and mood disorders.

The mounting evidence for neurogenesis in the adult hippocampus has fundamentally challenged the traditional view of brain development. The intense search for clues as to the functional significance of the new neurons has uncovered a surprising connection between neurogenesis and depression. In animal models of depression, neurogenesis is reduced, whereas many treatments for depression promote neurogenesis. We speculate on why the hippocampus, traditionally viewed as a memory structure, might be involved in mood disorders, and what specific role the new neurons might have in the pathogenesis of and recovery from depression. The proposed role of neurogenesis in contextual-memory formation predicts a specific pattern of cognitive deficits in depression and has important implications for treatment of this highly prevalent and debilitating disorder.

Anatomical gradients of adult neurogenesis and activity: young neurons in the ventral dentate gyrus are activated by water maze training.

Hippocampal function varies in a subregion‐specific fashion: spatial processing is thought to rely on the dorsal hippocampus, whereas anxiety‐related behavior relies more on the ventral hippocampus. During development, neurogenesis in the dentate gyrus (DG) proceeds along ventral to dorsal as well as suprapyramidal to infrapyramidal gradients, but it is unclear whether regional differences in neurogenesis are maintained in adulthood. Moreover, it is unknown whether young neurons in the adult exhibit subregion‐specific patterns of activation. We therefore examined the magnitude of neurogenesis and the activation of young and mature granule cells in DG subregions in adult rats that learned a spatial water maze task, swam with no platform, or were left untouched. We found that both adult neurogenesis and granule cell activation, as defined by c‐fos expression in the granule cell population as a whole, were higher in the dorsal than the ventral DG. In contrast, c‐fos expression in adult‐born granule cells, identified by PSA‐NCAM or location in the subgranular zone, occurred at a higher rate in the opposite subregion, the ventral DG. Interestingly, c‐fos expression in the entire granule cell population was equivalent in water maze‐trained rats and swim control rats, but was increased in the young granule cells only in the learning condition. These results provide new evidence that hippocampally‐relevant experience activates young and mature neurons in different DG subregions and with different experiential specificity, and suggest that adult‐born neurons may play a specific role in anxiety‐related behavior or other nonspatial aspects of hippocampal function.

The effects of running and of inhibiting adult neurogenesis on learning and memory in rats.

The presence of ongoing adult neurogenesis within the highly plastic hippocampal circuitry poses questions as to the relevance of new neurons to learning and memory. Correlational and causal evidence suggests that some, but not all, hippocampal tasks involve the new neurons. The evidence with regard to spatial learning in the water maze, one of the most commonly used hippocampal tasks, is contradictory. In this study we examined the effects of irradiation‐induced reduction in neurogenesis on spatial learning and another standard hippocampal task, contextual fear conditioning, in rats that experienced normal cage conditions or voluntary running. The results indicate that reduced neurogenesis had little effect on spatial learning but severely impaired contextual fear conditioning. It was suggested that compensatory mechanisms within the hippocampus may have contributed selectively to sparing of spatial function. Performance on the fear conditioning task was weakly related to enhanced neurogenesis or running. The results improve our understanding of the functional role of adult neurogenesis in behaving animals.

Adult hippocampal neurogenesis reduces memory interference in humans: opposing effects of aerobic exercise and depression

Since the remarkable discovery of adult neurogenesis in the mammalian hippocampus, considerable effort has been devoted to unraveling the functional significance of these new neurons. Our group has proposed that a continual turnover of neurons in the DG could contribute to the development of event-unique memory traces that act to reduce interference between highly similar inputs. To test this theory, we implemented a recognition task containing some objects that were repeated across trials as well as some objects that were highly similar, but not identical, to ones previously observed. The similar objects, termed lures, overlap substantially with previously viewed stimuli, and thus, may require hippocampal neurogenesis in order to avoid catastrophic interference. Lifestyle factors such as aerobic exercise and stress have been shown to impact the local neurogenic microenvironment, leading to enhanced and reduced levels of DG neurogenesis, respectively. Accordingly, we hypothesized that healthy young adults who take part in a long-term aerobic exercise regime would demonstrate enhanced performance on the visual pattern separation task, specifically at correctly categorizing lures as “similar.” Indeed, those who experienced a proportionally large change in fitness demonstrated a significantly greater improvement in their ability to correctly identify lure stimuli as “similar.” Conversely, we expected that those who score high on depression scales, an indicator of chronic stress, would exhibit selective deficits at appropriately categorizing lures. As expected, those who scored high on the Beck Depression Inventory (BDI) were significantly worse than those with relatively lower BDI scores at correctly identifying lures as “similar,” while performance on novel and repeated stimuli was identical. Taken together, our results support the hypothesis that adult-born neurons in the DG contribute to the orthogonalization of incoming information.

Computational modeling and empirical studies of hippocampal neurogenesis-dependent memory: Effects of interference, stress and depression

Prolonged stress causes dysregulation in the hypothalamic-pituitary-adrenal axis and may contribute to the pathogenesis of major depressive disorder (MDD). MDD is associated with pathological changes in several brain regions, particularly the prefrontal cortex and hippocampus. Evidence from animal research suggests that one of the earliest signs of pathological change after exposure to stress is a reduction in hippocampal neurogenesis. We therefore sought to test the prediction that people in the earliest stages of a first episode of depression would show selective memory deficits on neurogenesis-dependent tasks. Our computational model predicts that new neurons are important for representing distinct contexts; thus, when overlapping memories are learned over an interval of several days, during which time some neuronal turnover has taken place, the neurogenesis should reduce the potential for interference between the overlapping memories. At much shorter time scales, within the span of a single memory episode, rather than contributing to pattern separation, neurogenesis might play more of an integrative role in mediating contextual associative learning. Consistent with this, empirical evidence from animal studies suggests a role for the new neurons in forming complex event memories that bridge across time delays. This leads us to predict selective memory deficits on putative neurogenesis-dependent tasks in the earliest pre-clinical stages of a first episode of depression, before a clinical diagnosis has been made and prior to the development of more serious pathological brain changes. We present the results of new simulations with the model, lending further support to the prediction that neurogenesis reduces interference when memory events are separated by several days. We also report findings from an empirical study in which we tested a large number of undergraduates on a set of cognitive and memory tests from the CANTAB battery, and also administered neuropsychological inventories for stress, depression and anxiety. One of the subtests in the CANTAB battery, the delayed match to sample (DMS) task, was of particular interest as delayed non-match to sample has been found in animal studies to be dependent upon neurogenesis. Our empirical results indicate that as predicted, participants scoring high on the Beck Depression Inventory show a selective deficit on the DMS at long delays while performing on par with non-depressed participants on all other tasks. The potential to detect very early signs of major depression using simple neurogenesis-dependent cognitive tests could have important implications for the diagnosis and treatment of this debilitating and highly prevalent disorder.

Adult hippocampal neurogenesis and memory interference

Rats, subjected to low-dose irradiation that suppressed hippocampal neurogenesis, or a sham treatment, were administered a visual discrimination task under conditions of high, or low interference. Half of the rats engaged in running activity and the other half did not. In the non-runners, there was no effect of irradiation on learning, or remembering the discrimination response under low interference, but irradiation treatment increased their susceptibility to interference, resulting in loss of memory for the previously learned discrimination. Irradiated rats that engaged in running activity exhibited increased neuronal growth and protection from memory impairment. The results, which show that hippocampal cells generated in adulthood play a role in differentiating between conflicting, context-dependent memories, provide further evidence of the importance of neurogenesis in hippocampus-sensitive memory tasks. The results are consistent with computational models of hippocampal function that specify a central role for neurogenesis in the modulation of interfering influences during learning and memory.

Septo-temporal gradients of neurogenesis and activity in 13-month-old rats

Recent studies suggest that hippocampal function is partially dissociable along its septo-temporal axis: the septal hippocampus is more critical for spatial processing, while the temporal hippocampus may be more important for non-spatial-related behavior. In young adults, water maze training specifically activates new neurons in the temporal hippocampus, but it is unknown whether subregional differences are maintained in older animals, which have reduced neurogenesis levels. We therefore examined gradients of activity-related Fos expression and neurogenesis in 13-month-old rats and found that neurogenesis occurs relatively evenly throughout the dentate gyrus. Water maze experience significantly increased Fos expression in the suprapyramidal blade and Fos was highest in the septal pole of the dentate gyrus whether the animal learned a platform location, swam in the absence of a platform or remained in their cage. No Fos+ young neurons were found using typical markers of immature neurons. However, Fos expression in the subgranular zone, where adult-born neurons predominate, was disproportionally high in the temporal dentate gyrus. These findings indicate that adult-born neurons in the temporal hippocampus are preferentially activated compared with older neurons.