André A. Fenton

Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation

Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.

Storage of spatial information by the maintenance mechanism of LTP.

Analogous to learning and memory storage, long-term potentiation (LTP) is divided into induction and maintenance phases. Testing the hypothesis that the mechanism of LTP maintenance stores information requires reversing this mechanism in vivo and finding out whether long-term stored information is lost. This was not previously possible. Recently however, persistent phosphorylation by the atypical protein kinase C isoform, protein kinase Mzeta (PKMz), has been found to maintain late LTP in hippocampal slices. Here we show that a cell-permeable PKMz inhibitor, injected in the rat hippocampus, both reverses LTP maintenance in vivo and produces persistent loss of 1-day-old spatial information. Thus, the mechanism maintaining LTP sustains spatial memory.

PKMζ maintains spatial, instrumental, and classically conditioned long-term memories

How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMζ maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMζ activity. We then examined, using ZIP, the effect of PKMζ inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMζ inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMζ activity. Similarly, PKMζ inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMζ inhibition in the BLA impaired retention of classical conditioned stimulus–unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMζ inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMζ activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information.

Adult-born hippocampal neurons promote cognitive flexibility in mice.

The hippocampus is involved in segregating memories, an ability that utilizes the neural process of pattern separation and allows for cognitive flexibility. We evaluated a proposed role for adult hippocampal neurogenesis in cognitive flexibility using variants of the active place avoidance task and two independent methods of ablating adult‐born neurons, focal X‐irradiation of the hippocampus, and genetic ablation of glial fibrillary acidic protein positive neural progenitor cells, in mice. We found that ablation of adult neurogenesis did not impair the ability to learn the initial location of a shock zone. However, when conflict was introduced by switching the location of the shock zone to the opposite side of the room, irradiated and transgenic mice entered the new shock zone location significantly more than their respective controls. This impairment was associated with increased upregulation of the immediate early gene Arc in the dorsal dentate gyrus, suggesting a role for adult neurogenesis in modulating network excitability and/or synaptic plasticity. Additional experiments revealed that irradiated mice were also impaired in learning to avoid a rotating shock zone when it was added to an initially learned stationary shock zone, but were unimpaired in learning the identical simultaneous task variant if it was their initial experience with place avoidance. Impaired avoidance could not be attributed to a deficit in extinction or an inability to learn a new shock zone location in a different environment. Together these results demonstrate that adult neurogenesis contributes to cognitive flexibility when it requires changing a learned response to a stimulus‐evoked memory.

A critical role for α4βδ GABAA receptors in shaping learning deficits at puberty in mice

Puberty Impairs Plasticity While the existence of a period of reduced learning coinciding with the onset of puberty in mice is well characterized, the underlying cellular and molecular mechanisms remain unclear. Shen et al. (p. 1515) assessed the role of specific γ-aminobutyric acid type A (GABAA) receptors for restricting hippocampal plasticity during puberty. At puberty, but not in adults or the very young, GABA receptors containing the α4 and δ subunits were targeted perisynaptically to excitatory synapses, shunting the depolarizing current necessary for N-methyl-d-aspartate (NMDA) receptor activation. As a consequence, signal transmission was affected and spatial learning reduced. Learning incapacity observed during puberty is related to receptor location in the hippocampus. The onset of puberty defines a developmental stage when some learning processes are diminished, but the mechanism for this deficit remains unknown. We found that, at puberty, expression of inhibitory α4βδ γ-aminobutyric acid type A (GABAA) receptors (GABAR) increases perisynaptic to excitatory synapses in CA1 hippocampus. Shunting inhibition via these receptors reduced N-methyl- d-aspartate receptor activation, impairing induction of long-term potentiation (LTP). Pubertal mice also failed to learn a hippocampal, LTP-dependent spatial task that was easily acquired by δ−/− mice. However, the stress steroid THP (3αOH-5α[β]-pregnan-20-one), which reduces tonic inhibition at puberty, facilitated learning. Thus, the emergence of α4βδ GABARs at puberty impairs learning, an effect that can be reversed by a stress steroid.

Inactivating one hippocampus impairs avoidance of a stable room-defined place during dissociation of arena cues from room cues by rotation of the arena

Unilateral intrahippocampal injections of tetrodotoxin were used to temporarily inactivate one hippocampus during specific phases of training in an active allothetic place avoidance task. The rat was required to use landmarks in the room to avoid a room-defined sector of a slowly rotating circular arena. The continuous rotation dissociated room cues from arena cues and moved the arena surface through a part of the room in which foot-shock was delivered. The rat had to move away from the shock zone to prevent being transported there by the rotation. Unilateral hippocampal inactivations profoundly impaired acquisition and retrieval of the allothetic place avoidance. Posttraining unilateral hippocampal inactivation also impaired performance in subsequent sessions. This allothetic place avoidance task seems more sensitive to hippocampal disruption than the standard water maze task because the same unilateral hippocampal inactivation does not impair performance of the variable-start, fixed hidden goal task after procedural training. The results suggest that the hippocampus not only encodes allothetic relationships amongst landmarks, it also organizes perceived allothetic stimuli into systems of mutually stable coordinates. The latter function apparently requires greater hippocampal integrity.

Beyond memory, navigation, and inhibition: behavioral evidence for hippocampus-dependent cognitive coordination in the rat.

Injecting tetrodotoxin (TTX) into one hippocampus impaired avoidance of a place defined by distal cues while rats were on a slowly rotating arena. The impairment could be explained by a deficit in memory, navigation, or behavioral inhibition. Here, we show that the TTX injection abolished the ability of rats to organize place-avoidance behavior specifically when distal room and local arena cues were continuously dissociated. The results provide evidence that injecting TTX into one hippocampus specifically impaired the coordination of representations that support organized behavior because of the following: (1) rats normally coordinate separate room and arena avoidance memories; (2) the TTX injection spared spatial, relational, and representational memory, navigation, and behavioral inhibition; and (3) the TTX-induced impairment of place avoidance depended on the need to coordinate representations of local and distal stimuli.

Dynamic Grouping of Hippocampal Neural Activity During Cognitive Control of Two Spatial Frames

Hippocampal neurons represent two concurrent streams of spatial information by transiently organizing into subpopulations of coactive neurons and can reflect the most behaviorally relevant information at any given time.

Attention-Like Modulation of Hippocampus Place Cell Discharge

Hippocampus place cell discharge is an important model system for understanding cognition, but evidence is missing that the place code is under the kind of dynamic attentional control characterized in primates as selective activation of one neural representation and suppression of another, competing representation. We investigated the apparent noise (“overdispersion”) in the CA1 place code, hypothesizing that overdispersion results from discharge fluctuations as spatial attention alternates between distal cues and local/self-motion cues. The hypothesis predicts that: (1) preferential use of distal cues will decrease overdispersion; (2) global, attention-like states can be decoded from ensemble discharge such that both the discharge rates and the spatial firing patterns of individual cells will be distinct in the two states; (3) identifying attention-like states improves reconstructions of the rats path from ensemble discharge. These predictions were confirmed, implying that a covert, dynamic attention-like process modulates discharge on a ∼1 s time scale. We conclude the hippocampus place code is a dynamic representation of the spatial information in the immediate focus of attention.

Place navigation in rats with unilateral tetrodotoxin inactivation of the dorsal hippocampus : place but not procedural learning can be lateralized to one hippocampus

Lateralization of the Morris water maze task was examined by injecting 5 ng of tetrodotoxin (TTX) into one dorsal hippocampus (HPC) of chronically cannulated rats (n = 20). The task, acquired (A) during unilateral HPC block, was retrieved (R) during TTX blockade of the ipsi- (I) or contralateral (C) HPC. Escape latencies (in seconds) at 3 levels of acquisition and in the first 4-trial block of I or C retrieval suggest lateralization was absent after the first block (A = 49, I = 40, C = 44), partial after training to an efficient search strategy (A = 6, I = 9, C = 14), and complete after overtraining to goal-directed escape (A = 4, I = 4, C = 12), as further indicated by comparisons of A vs. R behavior and probe trials. The analyses also indicate that (a) HPC contributes to the acquisition but is unnecessary for retrieval of the procedural engram, (b) overtrained learning with one HPC or intact brain is similar, and (c) there is no left-right hemispheric specialization for place learning.