Hippocampal neurogenesis: Learning to remember

Abstract

Alzheimer's disease, the most prevalent form of dementia in the elderly, is characterized by progressive memory loss and cognitive dysfunction. It has become increasingly clear that while neuronal cell loss in the entorhinal cortex and hippocampus occurs in Alzheimer's disease, it is preceded by a long period of deficits in the connectivity of the hippocampal formation that contributes to the vulnerability of these circuits. Hippocampal neurogenesis plays a role in the maintenance and function of the dentate gyrus and hippocampal circuitry. This review will examine the evidence suggesting that hippocampal neurogenesis plays a role in cognitive function that is affected in Alzheimer's disease, will discuss the cognitive assessments used for the detection of Alzheimer's disease in humans and rodent models of familial Alzheimer's disease, and their value for unraveling the mechanism underlying the development of cognitive impairments and dementia.

Keywords: Alzheimer's disease; Behavior; Hippocampus; Learning and memory; Neurogenesis.

Fig. 1. Human Memory Domains

(a) Memory is divided into three primary functional domains; sensory memory, short-term memory and long-term memory. Long-term memory in turn can be divided into explicit, or conscious memory, and implicit, or unconscious memory. Implicit memory deals with procedural activities, like walking or tying ones shoe that are performed without conscious thought. In contrast explicit, or declarative, memory is memory for events (episodic memory) and facts (semantic memory).

Fig. 2. Hippocampal Circuitry

(a) Perforant path axons, extending from layer II of the entorhinal cortex (EC), make excitatory synaptic contacts with the dendrites of younger and older granule cells (GC). GCs send mossy fiber projections to the CA3 pyramidal cells, which, in turn send Schaffer collaterals to CA1 pyramidal cells. In addition CA3 cells on the same side form a dense associative network interconnecting with each other. CA3 pyramidal cells are also innervated by a direct input from layer II cells of the EC and CA1 pyramidal neurons receive a direct input from layer III cells of the EC. CA1 pyramidal neurons send axons out of the hippocampus innervating layer V of the EC. (b) Adult neurogenesis occurs in the subgranular layer (SGL) of the dentate gyrus (DG). Type I neural stem cells (NSC) give rise to intermediate progenitors (IP) called type IIa IP and type IIb IP cells. Type IIb cells are early committed neural progenitor cells (NPCs) and give rise to type III neuroblasts. Neuroblasts migrate into the granular layer where they mature into neurons. (c) In rats the number of GCs in the DG (∼1,000,000) is significantly larger than the number of EC cells projecting onto the DG (∼200,000). Thus the DG is sparsely activated (3% of granule cells activated) in response to stimuli from these inputs. Small changes in entorhinal input results in distinct, non-overlapping activation of the DG.

Fig. 3. Hippocampal Pattern Separation and Pattern Completion

(a) Pattern separation. Overlapping inputs from the entorhinal cortex, conveying information regarding context A and context B, are coded separately by the dentate gyrus. (b) Pattern completion. When a partial subset of cues for context A are presented, pattern completion induces retrieval of the whole memory.

Fig. 4. Maturation of Granule Cells

(a) In the first week after birth neural progenitor cells are distinguished by their irregular shape, immature spikes and synaptic silence. In week two they have migrated into the granule cell layer, developed spineless dendrites and slow GABAergic synaptic inputs. By the third week they start to form afferent connections from the perforant pathway of the entorhinal cortex and efferent connections to the CA3. Also a transition from GABAergic to glutamatergic synaptic inputs takes place. At this stage the developing neurons are highly excitable with high membrane resistance and high resting potential. Finally between weeks four and six these immature neurons exhibit stronger synaptic plasticity than mature dentate granule cells. They have a lower threshold for induction of LTP and higher LTP amplitude.

Fig. 5. Progression of Memory Impairments in preclinical, mild cognitive impairment and Alzheimer’s disease

The National Institute on Aging and the Alzheimer’s Association have created a standardized criteria for the cognitive profile of the three stages of AD memory deterioration; (1) preclinical Alzheimer’s disease (AD), (2) mild cognitive impairment (MCI) and (3) AD dementia. Preclinical AD individuals commonly display biomarkers predictive of AD progression, but they are either asymptomatic or have very subtle cognitive deficits. MCI individuals that are likely to progress to AD dementia commonly have impairments in episodic memory. They can also be impaired in one or more cognitive domain including semantic memory, executive function, attention, language and visuospatial skills. AD dementia individuals will display deficits in one or more of the cognitive domains affected in AD as well as amnestic deficits that include impairment in learning and recall of recently learned information. Non-amnestic impairments may also be present in language, visuospatial and executive function. Commonly progression to AD consists of memory deficits in episodic memory followed by semantic memory and finally deficits in executive function, attention, visuospatial memory, and verbal recall. However there is variation among individuals in the exact progression of cognitive dysfunction.

Fig. 6. Comparison of Human Versus Rodent Memory Assessment Methodologies

There are many behavioral tasks that are used to study memory in humans and rodents. Unfortunatley the same exact task can not be used to study both species, making behavioral studies a challenge for comparing rodents and humans. Here are several examples of tasks in humans and rodents used to study recognition memory, episodic memory, spatial learning, executive function and contextual conditioning, highlighting the challenging nature of comparing behavior. Recognition memory: humans are analyzed with the visual paired comparison task (analysis for memory of a previously seen image, as compared to a similar image (lure), a different image and the old image) and rodents using the novel object recognition task (assessing memory of a previously seen object). Episodic Memory: humas are analysed using a virtual reality city test (driving through the city to create episodic memory) or language based tests such as the Word List or Logical Memory recall tests while rodent tests include the What-Where-Which task (a modification of the novel object recoginition task to include a contextual component). Spatial Learning: humans are analyzed with the Money Road Map test (a table top spatial test) and rodents using the radial arm water maze task (extra maze cues guide swimming to an escape platform). Executive Function: humans are analyzed using the Wisconsin Card Sorting Task (sorting cards by shape, color or number) and rodents using reversal learning in the morris water maze (changing the escape platform location). Contextual Conditioning: humans are analyzed with a contextual conditioning task (specific images are paired with a negative stimulus) while rodent studies utilize the pattern separation task (context is paired with a negative stimulus).