James B. Aimone

New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?

The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time.

Potential role for adult neurogenesis in the encoding of time in new memories.

The dentate gyrus in the hippocampus is one of two brain regions with lifelong neurogenesis in mammals. Despite an increasing amount of information about the characteristics of the newborn granule cells, the specific contribution of their robust generation to memory formation by the hippocampus remains unclear. We describe here a possible role that this population of young granule cells may have in the formation of temporal associations in memory. Neurogenesis is a continuous process; the newborn population is only composed of the same cells for a short period of time. As time passes, the young neurons mature or die and others are born, gradually changing the identity of this young population. We discuss the possibility that one cognitive impact of this gradually changing population on hippocampal memory formation is the formation of the temporal clusters of long-term episodic memories seen in some human psychological studies.

Synapse formation on neurons born in the adult hippocampus

Although new and functional neurons are produced in the adult brain, little is known about how they integrate into mature networks. Here we explored the mechanisms of synaptogenesis on neurons born in the adult mouse hippocampus using confocal microscopy, electron microscopy and live imaging. We report that new neurons, similar to mature granule neurons, were contacted by axosomatic, axodendritic and axospinous synapses. Consistent with their putative role in synaptogenesis, dendritic filopodia were more abundant during the early stages of maturation and, when analyzed in three dimensions, the tips of all filopodia were found within 200 nm of preexisting boutons that already synapsed on other neurons. Furthermore, dendritic spines primarily synapsed on multiple-synapse boutons, suggesting that initial contacts were preferentially made with preexisting boutons already involved in a synapse. The connectivity of new neurons continued to change until at least 2 months, long after the formation of the first dendritic protrusions.

IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes.

Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

Computational Influence of Adult Neurogenesis on Memory Encoding

Adult neurogenesis in the hippocampus leads to the incorporation of thousands of new granule cells into the dentate gyrus every month, but its function remains unclear. Here, we present computational evidence that indicates that adult neurogenesis may make three separate but related contributions to memory formation. First, immature neurons introduce a degree of similarity to memories learned at the same time, a process we refer to as pattern integration. Second, the extended maturation and change in excitability of these neurons make this added similarity a time-dependent effect, supporting the possibility that temporal information is included in new hippocampal memories. Finally, our model suggests that the experience-dependent addition of neurons results in a dentate gyrus network well suited for encoding new memories in familiar contexts while treating novel contexts differently. Taken together, these results indicate that new granule cells may affect hippocampal function in several unique and previously unpredicted ways.

Adult neurogenesis: integrating theories and separating functions.

The continuous incorporation of new neurons in the dentate gyrus of the adult hippocampus raises exciting questions about memory and learning, and has inspired new computational models to understand the function of adult neurogenesis. These theoretical approaches suggest distinct roles for new neurons as they slowly integrate into the existing dentate gyrus network: immature adult-born neurons seem to function as pattern integrators of temporally adjacent events, thereby enhancing pattern separation for events separated in time; whereas maturing adult-born neurons possibly contribute to pattern separation by being more amenable to learning new information, leading to dedicated groups of granule cells that respond to experienced environments. We review these hypothesized functions and supporting empirical research and point to new directions for future theoretical efforts.

Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons

It is well known that Rett Syndrome, a severe postnatal childhood neurological disorder, is mostly caused by mutations in the MECP2 gene. However, how deficiencies in MeCP2 contribute to the neurological dysfunction of Rett Syndrome is not clear. We aimed to resolve the role of MeCP2 epigenetic regulation in postnatal brain development in an Mecp2-deficient mouse model. We found that, while Mecp2 was not critical for the production of immature neurons in the dentate gyrus (DG) of the hippocampus, the newly generated neurons exhibited pronounced deficits in neuronal maturation, including delayed transition into a more mature stage, altered expression of presynaptic proteins and reduced dendritic spine density. Furthermore, analysis of gene expression profiles of isolated DG granule neurons revealed abnormal expression levels of a number of genes previously shown to be important for synaptogenesis. Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis.

Cholinergic Input Is Required during Embryonic Development to Mediate Proper Assembly of Spinal Locomotor Circuits

Rhythmic limb movements are controlled by pattern-generating neurons within the ventral spinal cord, but little is known about how these locomotor circuits are assembled during development. At early stages of embryogenesis, motor neurons are spontaneously active, releasing acetylcholine that triggers the depolarization of adjacent cells in the spinal cord. To investigate whether acetylcholine-driven activity is required for assembly of the central pattern-generating (CPG) circuit, we studied mice lacking the choline acetyltransferase (ChAT) enzyme. Our studies show that a rhythmically active spinal circuit forms in ChAT mutants, but the duration of each cycle period is elongated, and right-left and flexor-extensor coordination are abnormal. In contrast, blocking acetylcholine receptors after the locomotor network is wired does not affect right-left or flexor-extensor coordination. These findings suggest that the cholinergic neurotransmitter pathway is involved in configuring the CPG during a transient period of development.

N2A: a computational tool for modeling from neurons to algorithms.

The exponential increase in available neural data has combined with the exponential growth in computing (“Moores law”) to create new opportunities to understand neural systems at large scale and high detail. The ability to produce large and sophisticated simulations has introduced unique challenges to neuroscientists. Computational models in neuroscience are increasingly broad efforts, often involving the collaboration of experts in different domains. Furthermore, the size and detail of models have grown to levels for which understanding the implications of variability and assumptions is no longer trivial. Here, we introduce the model design platform N2A which aims to facilitate the design and validation of biologically realistic models. N2A uses a hierarchical representation of neural information to enable the integration of models from different users. N2A streamlines computational validation of a model by natively implementing standard tools in sensitivity analysis and uncertainty quantification. The part-relationship representation allows both network-level analysis and dynamical simulations. We will demonstrate how N2A can be used in a range of examples, including a simple Hodgkin-Huxley cable model, basic parameter sensitivity of an 80/20 network, and the expression of the structural plasticity of a growing dendrite and stem cell proliferation and differentiation.

Modeling new neuron function: a history of using computational neuroscience to study adult neurogenesis

Adult neurogenesis is a sophisticated biological process whose function has remained a mystery to neuroscience researchers. To address this question, a number of unique modeling studies have explored the computational implications of adding new neurons to the adult dentate gyrus. Models of neurogenesis fall into two broad categories: abstract models that explore the function of new neurons in simple networks, and biologically based models that investigate the role of new neurons in networks based on the anatomy of the hippocampus. In this review, we summarize the strategies and results of these different modeling approaches, and we discuss their conclusions and limitations in the face of new biological findings.