In a new study from the University of Illinois at Chicago, researchers examining post-mortem brain tissue from people ages 79 to 99 found that new neurons continue to form well into old age.
The study provides evidence that this occurs even in people with cognitive impairment and Alzheimer’s disease, although neurogenesis is significantly reduced in these people compared to older adults with normal cognitive functioning.
They publish their results in the journal Cell Stem Cell.
The idea that new neurons continue to form into middle age, let alone past adolescence, is controversial, as previous studies have shown conflicting results.
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.
Adult neurogenesis is instrumental for hippocampal function
Deficits in neurogenesis may cause/exacerbate Alzheimer’s disease cognitive failure
Enhancing adult neurogenesis could be a therapeutic target for Alzheimer’s disease
Alzheimer’s disease is characterized by a progressive loss of memory, the failure to learn or retain new information and the deterioration of cognitive function.
Increasing evidence suggests that memory deficits develop over decades before they are detectable as mild cognitive impairments (MCI).
As aging continues some of these MCI patients will progress into Alzheimer’s disease (AD) dementia.
While extensive research in the last three decades unraveled the genetic constituents that are linked to familial Alzheimer’s disease, little is known about how learning and memory impairments develop, and the molecular substrates underlying the vulnerability of the entorhinal-hippocampal circuitry.
The generation of new neurons and glia in the adult hippocampus is increasingly implicated in forms of learning and memory.
New neurons are added to the granular cell layer of the dentate gyrus throughout life and are being recruited in greater amounts following experience, learning and exercise (Deng et al., 2010).
In turn, deficits in neurogenesis over time may compromise hippocampal function, gradually leading to memory deficits.
Numerous studies suggest that neurogenesis is impaired in mouse models of familial AD (for review (Lazarov and Marr, 2010)).
However it is not clear how hippocampal neurogenesis and its gradual decline with age contribute to the cognitive dysfunction in AD.
In search for a connection between AD and adult hippocampal neurogenesis one may struggle with comparative behavioral assessment in humans and mouse models.
This review will attempt to connect our basic understanding of mechanisms of learning and memory with memory dysfunction in Alzheimer’s disease.
In addition, it will critically consider the current evidence concerning the role of neurogenesis in the development of cognitive deficits and Alzheimer’s disease.Go to:
The role of the hippocampus in learning and memory
Memory and learning are essential components of human existence; they provide the framework for everyday activities and invest long-term meaning into significant events.
Understanding the mechanism behind how memory works gives us insight into the fundamental nature of humanity.
Extensive study has revealed that memory can be divided into functional segments; sensory memory, short term memory (working memory) and long term memory (Fig. 1).
Chosen short term memory traces are converted to long-term memory in a process called memory consolidation (McGaugh, 1966, Dudai, 2012, Kitamura and Inokuchi, 2014).
How the brain determines that some information is necessary and should be stored, while other can be discarded, is a fascinating enigma.
Such long-term memory for facts (semantic memory) and events (episodic memory) is referred to as explicit (declarative) memory.
This is in contrast to implicit (procedural) memory, which is required for perceptual and motor skills that are completed without conscious thought.
Implicit memory relies mostly on brain areas implicated in motor function, such as, the cerebellum and the striatum, while explicit memory involves the hippocampus and related cortices.
Studying patients with amnesic symptoms first hypothesized the role of the hippocampus in explicit memory, the most famous patient being Henry Molaison (H.M).
Henry Molaison had a portion of his medial temporal lobe removed, including the hippocampus, in an effort to suppress epilepsy symptoms.
This procedure left him unable to store or retrieve new memories (Scoville and Milner, 1957). Inspired by this early tragedy, extensive research has confirmed an essential role for the hippocampus in both storing and retrieving new memories as well as in spatial navigation.
However the exact mechanisms and functions of individual parts of the hippocampal circuitry are still under debate.
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).
Hippocampal Circuitry
Sensory information is fed into the dentate gyrus (DG) of the hippocampus by projections from the entorhinal cortex, which in turn receives input from multiple cortical and sensory areas (Fig. 2).
Medial perforant path input from the entorhinal cortex into the DG mediates spatial information, via activation of NMDA receptors, while the lateral perforant path mediates visual object information (e.g. odors or objects) through activation of opioid receptors (Hunsaker et al., 2007).
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.
In rats the number of granule cells in the dentate gyrus of the hippocampus (∼1,000,000) is significantly larger than the number of entorhinal cells projecting onto the DG (∼200,000) (Amaral et al., 1990).
Thus the DG is sparsely activated (3% of granule cells activated) in response to stimuli from these inputs (Chawla et al., 2005) and as a result small changes in entorhinal input results in distinct, non-overlapping activation of the DG (O’Reilly and McClelland, 1994).
In the DG interneurons also provide contribution to the circuitry; granular cells are interconnected by excitatory interneurons located in the hilus and a layer of inhibitory interneurons provides recurrent inhibition (Lisman et al., 2005, Myers and Scharfman, 2011, Scharfman and Myers, 2012).
In contrast to the DG, whose primary input is the entorhinal cortex, the CA3 region of the hippocampus, receives multiple excitatory inputs; from granule cell mossy fibers in the DG (Blackstad et al., 1970, Swanson et al., 1978), directly from layer II of the entorhinal cortex (via the perforant path) (Witter, 1993) and through recurrent collateral input from CA3 neurons themselves (Amaral, 2007).
The recurrent collateral input in the CA3 suggests that this region has auto-associative properties (for review (Rolls, 2013)).
This means that groups of coactive CA3 neurons could have increasingly strengthened connections as a result of synaptic plasticity.
The unique circuitry of the hippocampus has lead to several hypotheses regarding its specific role in explicit memory, many of these arising from quantitative computational theories that have then been tested through genetic and molecular means (for review (Kesner and Rolls, 2015)).
Hippocampal neurogenesis
The hippocampus is one of only a few regions in the adult brain, including the sunventricular zone (in rodents) and, recently shown in humans, the striatum, that continues to produce new neurons (Ernst et al., 2014). In the bottom third of the DG of the hippocampus, the subgranular layer (SGL), type I neural stem cells (NSC) give rise to type IIa, type IIb and type III neural progenitor cells (NPC), and neuroblasts that mature into neurons and migrate into the granule cell layer (GCL) (Fig. 4). These various cell types can be identified by a stereotypic pattern of protein expression (for review (Lazarov et al., 2010, Kempermann et al., 2015)).
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.
Adult neurogenesis is a form of hippocampal plasticity with NPCs bearing little resemblance to their mature counterparts.
Maturation from the NPC stage to mature neurons follows a specific pattern of events, with developing neurons having distinct firing and physical characteristics from their mature counterparts (for review (Aimone et al., 2010, Deng et al., 2010, Aimone et al., 2014), Fig. 4).
In the first week after birth NPCs are distinguished by their irregular shape, immature spikes and synaptic silence. In week two they have migrated into the GCL, 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 the induction of LTP and higher LTP amplitude.
Newly born neurons can account for up to ten percent of the granule cell population in the hippocampus (Imayoshi et al., 2008).
The role that new neurons play in the function of the dentate gyrus in memory formation remains controversial.
Adult born neurons have been shown to modulate signal processing in the DG and to be necessary for pattern separation specifically (for review (Aimone et al., 2011, Sahay et al., 2011b, Kropff et al., 2015)).
Using a combination of methods to decrease or enhance neurogenesis in behavioral tasks such as the RAWM, contextual fear discrimination learning and two-choice spatial discrimination, studies have shown that animals with ablated neurogenesis had deficits in their ability to discriminate between highly similar situations and animals with enhanced neurogenesis improved in such tasks (Clelland et al., 2009, Creer et al., 2010, Sahay et al., 2011a, Kheirbek et al., 2012, Nakashiba et al., 2012, Tronel et al., 2012).
However, the changing characteristics of newly born neurons over time leaves the exact developmental phase at which they are required for pattern separation unclear, especially because in these studies alterations in neurogenesis were started weeks before training and lasted throughout the testing period.
Similarly because testing and training are closely linked it is not possible to determine if adult neurogenesis is required for task acquisition, retrieval or both.
A more detailed temporal analysis of adult neurogenesis in pattern separation will be important to understand the functional role of new neurosn in the DG in their entirety.
In addition to their synaptic connection with EC layer II and CA3; new neurons indirectly activate contralateral granule neurons, via innervation of hilar mossy cells.
In addition, they innervate basket interneurons, which consecutively inhibit granule neurons (Freund and Buzsaki, 1996).
Depletion of new neurons results in enhanced spontaneous γ-frequency burst amplitude in the DG. This suggests that young neurons may inhibit or destabilize the hippocampal circuitry (Lacefield et al., 2012).
Interestingly, recent evidence suggests that removal of NPCs also plays a role in hippocampal plasticity. For example, Dupret and colleagues (2007) suggest that spatial learning promotes the survival of relatively mature neurons, concomitantly with the apoptosis of more immature cells, as well as the proliferation of NPCs (Dupret et al., 2007).
Thus, they suggest that blocking apoptosis impairs memory. Intriguingly, neurogenesis has been implicated in the modulation of forgetting and memory clearance as well (Feng et al., 2001, Akers et al., 2014).
Important key characteristic of NPCs and new neurons is their modulation by numerous local, systemic and environmental factors, including but not limited to neurotransmitters, hormones, cytokines, as well as learning, exercise, environmental enrichment and stress.
Modulation by these factors will determine the extent of NPCs and of new neurons that will join the GCL, and play an important role in the resulting hippocampal structure and function.
Specific factors may affect particular neurogenic populations and affect neurogenesis to a different extent. For example, it has been hypothesized that there is a critical period in which an enriched environment results in enhanced survival and population response of adult born neurons. However the exact window is controversial with some suggesting it lies at two to four weeks following birth of new neurons (Tashiro et al., 2007, Gu et al., 2012).
Significantly, activity-dependent promotion of neurogenesis has also been shown to occur following deep brain stimulation of the entorhinal cortex.
Stimulation of the entorhinal cortex promotes proliferation in the SGL and NPCs mature and integrate into the circuitry of the hippocampus (Stone et al., 2011).
These various forms of modulation impacting neurogenesis, including adaptation to novelty, learning and activity dependent stimulation, all demonstrate that adult neurogenesis has an important role in neural plasticity.
Importantly, neurogenesis is recruited for learning, and plays an important role in many aspects of hippocampus-dependent memory, as discussed in detail below.
Learning in tasks such as the MWM task have been shown to promote survival of relatively mature neurons, apoptosis of more immature cells, and finally, proliferation of neural precursors.
Blocking apoptosis impairs memory and inhibits learning-induced cell survival and cell proliferation (Dupret et al., 2007). Arruda-Carvaloho et al. (2011) utilized diphtheria toxin to selectively ablate predominantly mature, adult born neurons either before or after learning.
They observed deficits in contextual fear and water maze tasks when ablation was performed following learning but not before. Taken together, the remarkable plasticity of new neurons allows for a dynamic system controlling learning and memory and it will be important to consider how such plasticity stands up to aging and AD.
The UIC study is the first to find evidence of significant numbers of neural stem cells and newly developing neurons present in the hippocampal tissue of older adults, including those with disorders that affect the hippocampus, which is involved in the formation of memories and in learning.
“We found that there was active neurogenesis in the hippocampus of older adults well into their 90s,” said Orly Lazarov, professor of anatomy and cell biology in the UIC College of Medicine and lead author of the paper.
“The interesting thing is that we also saw some new neurons in the brains of people with Alzheimer’s disease and cognitive impairment.”
She also found that people who scored better on measures of cognitive function had more newly developing neurons in the hippocampus compared to those who scored lower on these tests, regardless of levels of brain pathology.
Lazarov thinks that lower levels of neurogenesis in the hippocampus are associated with symptoms of cognitive decline and reduced synaptic plasticity rather than with the degree of pathology in the brain.
For patients with Alzheimer’s disease, pathological hallmarks include deposits of neurotoxic proteins in the brain.
“In brains from people with no cognitive decline who scored well on tests of cognitive function, these people tended to have higher levels of new neural development at the time of their death, regardless of their level of pathology,” Lazarov said.
“The mix of the effects of pathology and neurogenesis is complex and we don’t understand exactly how the two interconnect, but there is clearly a lot of variation from individual to individual.”
Lazarov is excited about the therapeutic possibilities of her findings.
“The fact that we found that neural stem cells and new neurons are present in the hippocampus of older adults means that if we can find a way to enhance neurogenesis, through a small molecule, for example, we may be able to slow or prevent cognitive decline in older adults, especially when it starts, which is when interventions can be most effective,” Lazarov said.
New neurons continue to be formed in the hippocampus into the tenth decade of life, even in people with mild cognitive impairment and Alzheimer’s disease. The image is credited to Orly Lazarov, et al.
Lazarov and colleagues looked at post-mortem hippocampal tissue from 18 people with an average age of 90.6 years.
They stained the tissue for neural stem cells and also for newly developing neurons.
They found, on average, approximately 2,000 neural progenitor cells per brain.
They also found an average of 150,000 developing neurons.
Analysis of a subset of these developing neurons revealed that the number of proliferating developing neurons is significantly lower in people with cognitive impairment and Alzheimer’s disease.
Lazarov is interested in finding out whether the new neurons she and her team discovered in the brains of older adults are behaving the way new neurons do in younger brains.
“There’s still a lot we don’t know about the maturation process of new neurons and the function of neurogenesis in older brains, so it is difficult to predict how much it might ameliorate the effects of cognitive decline and Alzheimer’s disease.
The more we find out, the better able we will be to develop interventions that may help preserve cognitive function even in people without Alzheimer’s. We all lose some cognitive function as we age – it’s normal.”
Funding: This research was supported by grants from the National Institute on Aging (AG033570, AG033570-S1, S2, AG060238, AG62251, AG061628, AG17917, AG34374, UH2NS100599) and the Canadian Institutes of Health Research (MT-14037, MOP-81112).
Matthew Tobin, Kianna Musaraca, Ahmed Disouky, Aashutosh Shetti and Abdullah Bheri of UIC; William Honer of the University of British Columbia, Vancouver; and Namhee Kim, Robert Dawe, David Bennett and Konstantinos Arfanakis of Rush University Medical Center are co-authors on the paper.
Source:
University of Illinois
Media Contacts:
Jackie Carey – University of Illinois
Image Source:
The image is credited to Orly Lazarov, et al.
Original Research: Open access
“Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer’s Disease Patients”. Orly Lazarov et al.
Cell Stem Cell. doi:10.1016/j.stem.2019.05.003
