Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation

Abstract

The hippocampus is one of the few areas of the rodent brain that continues to produce neurons postnatally. Neurogenesis reportedly persists in rats up to 11 months of age. Using bromodeoxyuridine (BrdU) labeling, the present study confirms that in the adult rat brain, neuronal progenitor cells divide at the border between the hilus and the granule cell layer (GCL). In adult rats, the progeny of these cells migrate into the GCL and express the neuronal markers NeuN and calbindin-D28k. However, neurogenesis was drastically reduced in aged rats. Six-to 27-month-old Fischer rats were injected intraperitoneally with BrdU to detect newborn cells in vivo and to follow their fate in the dentate gyrus. When killed 4-6 weeks after BrdU labeling, 12- to 27-month-old rats exhibited a significant decline in the density of BrdU-positive cells in the granule cell layer compared with 6-month-old controls. Decreased neurogenesis in aging rats was accompanied by reduced immunoreactivity for poly-sialylated neural cell adhesion molecule, a molecule that is involved in migration and process elongation of developing neurons. When animals were killed immediately (12 hr) after BrdU injection, significantly fewer labeled cells were observed in the GCL and adjacent subgranular zone of aged rats, indicative of a decrease in mitotic activity of neuronal precursor cells. The reduced proliferation was not attributable to a general aged-related metabolic impairment, because the density of BrdU-positive cells was not altered in other brain regions with known mitotic activity (e.g., hilus and lateral ventricle wall). The decline in neurogenesis that occurs throughout the lifespan of an animal can thus be related to a decreasing proliferation of granule cell precursors.

Serotonin and Hippocampal Neurogenesis

“…We and others have demonstrated that these precursor cells divide and produce daughter cells that differentiate into granule neurons. These cells become incorporated into the gcl and express markers of mature granule neurons, including neuron specific enolase (NSE), the calcium binding protein calbindin, the NMDA receptor subunit NR1, and Neuronal Nuclei (NeuN): within 3 weeks of DNA synthesis (Cameron et al 1993a(Cameron et al , 1993bOkano et al 1993;Kuhn et al 1996). Cells produced in adulthood receive synaptic input and extend axons into the mossy fiber pathway (Kaplan and Hinds 1977;Kaplan and Bell 1984;Stanfield and Trice 1988).…”

“…The majority of these cells differentiate into mature neurons . In the aged animal, however, the production of new granule neurons diminishes significantly in both the rodent and primate (Kuhn et al 1996;Gould et al 1999a).…”

“…A considerable body of evidence suggests that 5HT may stimulate the production of neurons in the dentate gyrus. First, conditions that are associated with diminished granule cell genesis, such as malnutrition (Debassio et al 1996), aging (Kuhn et al 1996;Gould et al 1999), high corticosterone (Cameron and Gould 1994), stress , and NMDA receptor activation (Cameron et al 1995), also decrease the density of 5HT fibers or 5HT1A receptors, or inhibit the release of 5HT in the dentate gyrus (Blatt et al 1994;Chalmers et al 1993;McKittrick et al 1995;Nishimura et al 1995;Meijer and deKloet 1994;Watanabe et al 1993;Tao and Auerbach 1996;Whitton et al 1994;Nyakas et al 1997). Second, experimental manipulations that stimulate granule cell genesis, such as seizures (Parent et al 1997), adrenalectomy (Cameron and Gould 1994), and NMDA receptor antagonist treatment (Cameron et al 1995), also increase the density of 5HT1A receptors or the release of 5HT in the dentate gyrus (Hayakawa et al 1994;Burnet et al 1995;Whitton et al 1994;Kuroda et al 1994).…”

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

“…Ageing is the greatest negative regulator of hippocampal neurogenesis (Kuhn et al, 1996), and adult neurogenesis may be required for hippocampal-dependent learning and memory (Zhao et al, 2008). Increased neurogenesis in rodents is seen following ischaemia (Takagi et al, 1999), stroke (Darsalia et al, 2005) and after seizures (Parent et al, 1997).…”

Neural stem cells: mechanisms and modeling

“…In the early 1990s, neural stem cells (NSCs) were successfully isolated from mammalian brains (Reynolds and Weiss, 1992). Shortly thereafter, by means of powerful new markers for dividing cells, such as BrdU (Kuhn et al, 1996), NSCs were eventually determined to be largely focused in two regions in the adult brain, the subgranular zone (SGZ) of the dentate gyrus of the hippocampus and the subventricular zone (SVZ) of the forebrain. All these cells are characterized by the capabilities of self-renewing and producing neurons and glial cells through asymmetric division.…”