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Abstract

Adult neurogenesis has been a focus within the past few years because it is a newly recognized form of neuroplasticity that may play significant roles in behaviors and recovery process after disease. Mammalian adult neurogenesis could be found in two brain regions: hippocampus and subventricular zone (SVZ). While it is well established that hippocampal neurogenesis participates in memory formation and anxiety, the physiological function of SVZ neurogenesis is still under intense investigation. Recent studies disclose that SVZ neurogenesis is under regulation of reproductive cues like pheromones. Reciprocally, the newborn neurons may exert their effect on reproductive and maternal behaviors. This review discusses recent understanding of the interrelationship between neurogenesis and reproduction. The studies highlighted in this review illustrate the potential importance of neurogenesis in reproductive function and will provide new insights for the significance of adult neurogenesis.

Keywords

Neurogenesis Reproductive function Mammalian brain Interrelationship

Introduction

Discovery of endogenous neural stem cells in the adult mammalian brain is a spectacular event because this discovery has revolutionized the traditional view that the mammal central nervous system (CNS) does not generate new neurons in adulthood (40). Hopes for applications like nervous tissue replacement and enhancement of cognitive functions are inspired by neurogenesis and neural stem cells (17), but basic research issues remain to be addressed before such applications. For example, what are the function and physiological significance of neurogenesis? Which factor promotes/suppresses neurogenesis? Within the past few years, increasing reports and efforts are contributing to this burgeoning field.

Adult neurogenesis in mammalian brain takes place mainly in two regions: hippocampus and subventricular zone (SVZ) (20). Neurogenesis in the hippocampus was related to conditioning (learning) and therapeutic effect of psychotropic drugs (71,95). In contrast, the function of SVZ neurogenesis is currently obscure. Emerging evidence has shown that reproductive action or cues (pheromones) could regulate neurogenesis in the olfactory system and SVZ (69,93). Reciprocally, significance of newborn neurons in reproductive functions was recently disclosed. The aim of this review is to illustrate the complex interplay between neurogenesis and reproduction, which is one of the important biological functions. Several aspects will be discussed, including adult neurogenesis in mammals, regulation of rodent sexual behaviors, and interrelationship between neurogenesis and reproduction. As there are relatively few studies exploring the relationship between neurogenesis and reproduction, several key studies will be highlighted in this review.

Adult Neurogenesis in the Brain

Neural stem cells are undifferentiated cells that have proliferative potential and are capable of giving rise to the components of the nervous system (104). Stem cells are defined to contain two key characteristics: 1) the ability for self-renewal and 2) the ability to generate at least two types of cells/progenies (multipotency). While self-renewal is the essential criterion for the definition of stem cells, there are controversies regarding the multipotency. Certain groups consider multipotency as unnecessary and the identity of stem cells depends only on self-renewal (110). However, it is generally agreed that unipotent (ability to produce one type of differentiated cell) cells are daughter cells with reduced stem cell properties and thus they are termed “progenitor” cells but not “stem” cells (104).

Self-renewal or replenish is the principle characteristic of stem cells (113). To fulfill this, at least one of the divided cells (daughter cell) after cell division should be identical to the mother cell. If the division generates two cells that are identical to each other, the process is described as “symmetric.” In contrast, asymmetric division gives rise to a daughter cell that is identical to the mother cell and another one that is more determined to a certain cell lineage (e.g., neuronal or glial cell lineage). In case the daughter cells are identical to each other but not to the mother cell, the division is still symmetric but the mother cell could not self-renew and it may not be considered as a stem cell.

One of the main differences between stem cells and progenitor cells is the unlimited self-renewal of stem cells (81). On the other hand, progenitor cells are described as “transiently amplifying” cells as they are more proliferative than the relatively dormant stem cells. According to Seaberg and ver der Kooy (92), there is an increasing trend to ignore the rigorous definitions of stem cell and progenitor cells. However, biological and functional difference between stem and progenitor cells does exist, such as difference in unlimited self-renewal and multipotency, and thus the concepts of stem and progenitor cells should be kept for testing specific hypothesis.

Radial glia is a type of cell that plays a critical role in brain development. It plays two roles during the process: 1) serving as a source of neural progenitor cells and 2) providing a migration structure that guides newly generated cells (81). In other words, radial glial cells act as stem cells/proliferative cells during the developmental process. Continuous neuron production (neurogenesis) occurs during brain development and radial glia cells are highly proliferative during this period. By extending fibers from the ventricular zone radially, radial glia serves as the guidance structure for the newborn neurons to migrate to appropriate location to form the cortex. After the brain development, radial glial cells in the adult neurogenic regions [including SVZ and hippocampus] persist into adulthood (3) while those in the nonneurogenic regions transforms into astrocytes.

As Alvarez-Buylla et al. suggested (3), glial fibrillary acidic protein (GFAP, a cellular marker of astrocyte)-positive cells residing in the SVZ and hippocampus could be the source of stem cells in the adult neurogenic region. This speculation was supported by several evidences. When GFAP-expressing cells in the adult rodent brain were killed by ganciclovir, stem cell culture showed a 20-fold decrease of neural stem cells (75). On the other hand, when cytostatic drug cytosine arabinoside (Ara-c) was used to ablate cell proliferation in adult SVZ and hippocampus, cell proliferation restored after the cease of drug treatment and the first kind of cells to appear were GFAP-positive cells (27). Furthermore, when only astrocytes in the SVZ were transfected with a reporter gene (green fluorescent protein), newborn neurons with the reporter gene expression could be found in the olfactory bulb. Additionally, astrocytes derived from the SVZ were able to form neurospheres of multipotent neural progenitor cells (27). It was suggested that the astrocytes in the SVZ and hippocampus were the likely source of neural stem cells, and the developmental lineage of the neural stem cells was proposed to be from neuroepithelial cells to radial glia during the developmental process and then astrocytes in the adult neurogenic regions (3). Although GFAP-expressing cells were supposed to be the source of adult neural stem cells, the distinction between GFAP-expressing stem cells and astrocyte was highlighted by Morshead and van der Kooy (76). Because both the differentiated astrocytes and the stem cells express GFAP, it is difficult to identify neural stem cells by only employing this marker. Functional difference between these two populations of cells may be present and thus “astrocyte” may not be an appropriate term for neural stem cells in the SVZ and hippocampus.

Neurogenesis in Specific Regions

Olfactory System

The olfactory system contains two regions that are neurogenic in adulthood: the olfactory epithelium and olfactory bulb (67,93). The amygdala, which is involved in emotional regulation, is tightly related to the olfactory system and neurogenesis could also be found (33).

Olfactory Epithelium/Mucosa

Olfaction is a sensation not only related to appetite but also related to different physiological phenomena, including provision of information related to danger and emotional regulation (7). There are numerous reports showing adult neurogenesis in olfactory epithelium (67). The functional significance of adding new neurons in the olfactory mucosa is still obscure and it is speculated that because olfactory receptor neurons are exposed to different chemical agents for olfaction, they are susceptible to the neurotoxicity of these substances and are required to be replaced constantly to allow olfaction to function.

There are three types of cells in the olfactory mucosa: basal cells, supporting cells, and olfactory sensory neurons. Basal cells, or globose basal cells, are transiently amplifying cells that are supposed to generate olfactory sensory neurons (50), which account for higher that 90% of proliferative cells in the olfactory mucosa. Sustantacular cells, which are nestin (an intermediate filament expressed in many CNS precursors)-expressing cells, were proposed to be the counterpart of radial glial cells in other CNS neurogenic zones. As mentioned previously, radial glial cells have dual roles in giving rise to progenitor cells and providing guidance structure for neuronal migration, and the supporting sustantacular cells may also play such roles in the olfactory epithelium (28). Chen et al. (21) also demonstrated that the globose basal cells in culture condition showed the ability to give rise to different cell types, just as neural progenitor cells in other CNS regions. Taken together, cell proliferation in the olfactory epithelium may mirror neurogenesis that takes place in other regions: stem cells (sustantacular cells) of this system generates transient amplifying globose cells and the globose cells subsequently give rise to neurons or neural precursors (olfactory sensory neurons). The neural precursors later integrate into the existing system for physiological function. Although the actual roles of these cells in olfactory epithelium neurogenesis still require confirmation, this provides insights for utilization of olfactory mucosa as a reference for the state of neurogenesis in the CNS.

Regulation of olfactory mucosa neurogenesis is contributed by various factors, ranging from physiological manipulations to molecular level of influence. For example, axonal injury of the olfactory receptor neurons caused axonal degeneration and depletion of cell proliferation in the olfactory mucosa (39). Interestingly, 1 week after the damage, proliferation of basal cells was detected and the gross structure of the olfactory mucosa returned to normal 1 month after the ablation. The reconstituted mucosa was later found to be functional and could response to odor (24). Naris occlusion was also shown able to decrease neurogenesis in olfactory mucosa and the effect was reversible (31). These studies demonstrate the regenerative potential of the olfactory epithelium and the influence of physical damage on cell proliferation. At the molecular level, proteins like leukocyte inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and other factors were shown to influence globose basal cells in different aspects like cell proliferation, differentiation, and survival (79). It is expected that the various factors will converge by influencing key regulators of neurogenesis, such as transcription factors. For instance, Mash1 is one of the transcription factors important in the mucosa and highly expressed in basal cells. When Mash1 was eliminated in animals or blocked in culture conditions, neurogenesis of the olfactory mucosa or neural progenitor cells was inhibited (96). The list of factors and transcription factors that have an effect on neurogenesis is still expanding and the exact mechanisms remain to be elucidated. Further study on how the factors affect neurogenesis will provide insight on the regulation of neurogenesis and potential application.

Subventricular Zone and Olfactory Bulb

Apart from the olfactory mucosa, neurogenesis in the olfactory system also takes place in the olfactory bulb, which is located within the CNS. New neurons are added into the olfactory bulb network in the form of interneurons in the granule cell layer and periglomerular region. However, the major source of the neural progenitor cells is located outside the olfactory bulb. The precursor cell population is located at the lateral wall of the lateral ventricles, namely, SVZ (20,48). The SVZ is defined as a one- to two-cell-thick region from the lateral ventricle. After cell proliferation in the SVZ, new cells differentiate into neuronal lineage that migrates towards the olfactory bulb through the rostral migratory stream (RMS), which is an anatomical structure showing “chain migration.” Differentiation into interneurons takes place in the olfactory bulb and new circuitry is established within the olfactory bulb (112).

The walls of lateral ventricles are formed by a layer of ependymal cells, and astrocyte-like precursor cells are found in intimate contact with ependymal cells. It is speculated that the ependymal cells bear crucial regulatory functions in neurogenesis (64). For instance, antagonists of bone morphogenetic proteins (BMPs) are secreted by these cells, which promote neurogenesis but not generation of glial cells (gliogenesis).

As described previously, neurogenesis in the SVZ involves three types of cells: astrocyte-like stem cells (named B cells), transiently amplifying progenitor cells (C cells), and neural progenitors, which are confined to neuronal lineage (A cells) (26). There were debates about the source of neural stem cells in SVZ: which cell type, ependymal or astrocyte-like cells, is the stem cell? Because both cell types express GFAP and are able to proliferate, there is a chance that neurons are born from each of them. To address this issue, van der Kooy and coworkers have dissected the ependymal cells and found that this type of cell was unipotent and only glial cells were produced in vitro. In contrast, cells dissected below the ependymal layer (i.e., SVZ) could produce multiple type of progenies (22). Thus, it was confirmed that the astrocyte-like cells are the sources of stem cells in the SVZ.

When proliferative marker bromodeoxyuridine (BrdU) was injected to label actively proliferative cells, the transiently amplifying C cells were the most commonly labeled cells in the SVZ (26). Thus, they represent the largest pool of proliferative cells in this region. The immediate progeny of C cells are A cells, which are migratory neurons. Being different from C cells, A cells could be labeled with doublecortin (DCX), which is a protein related to neuronal migration and differentiation. To distinguish A, B, and C cells, different cellular markers are used in immunostaining method. For instance, GFAP and nestin are the markers of stem cells (B cells); C cells express Pax6 (41); A cells are characterized by DCX and polysialylated form of the neural cell adhesion molecule (PSA-NCAM) (26). Apart from neurons, cells expressing Olig2 (a marker of oligodendroglial cell precursor) were found in the SVZ (41). However, whether these populations of cells are from the common source with neural stem cells is unknown yet. The Olig2-positive cells may not enter the RMS and migrate to the olfactory bulb, and may become oligodendrocyte in other regions in the brain.

The newly generated neuronal progenitors (A cells) move from the SVZ to olfactory bulb in forms of chain migration, which is a unique migrating pattern that does not require a glial cell guidance (66). In the RMS, a cell will extend a process along the moving direction, which serves as a guiding structure for the movement of another cell, which in turn repeats the same procedure for another cell. During the migration, A cells continue to divide but with a much lower rate than in the SVZ (73). The movement direction is generally unidirectional to the olfactory bulb. After reaching the olfactory bulb, the unidirectional movement is changed. Immature neurons migrate to the granule cell layer and perioglomerular region radially from the center of the olfactory bulb. Neurons mature in the olfactory bulb and three types of interneurons are generated there: one type located in the granule cell layer and two types in the periglomerular region. Most of the new cells are granule cells (~95%) and produce GABA. The remaining 5% of new cells are located in the periglomerular region and synthesize dopamine as neurotransmitter. Mitral cells and tufted cells are the neurons that form synapse with the olfactory sensory neurons and they are not generated in adulthood (57). The functional significance of neurogenesis in the olfactory bulb is still under investigation and the role of the newly generated neurons remains obscure yet.

Amygdala

The amygdala is intimately connected to the olfactory system as fibers from the olfactory tract project directly to the amygdala (60). When comparing with the hippocampus and SVZ, information about neurogenesis in the amygdala is still scarce. Until now there is has been no direct evidence showing the function of new neurons in the amygdala. It is shown by Fowler and colleagues (32) that gonadotrophin hormone, which affects sexual behaviors, also affects neurogenesis in the amygdala. It is hypothesized that new cells in the amygdala contribute to reproductive functions and behaviors. Because this brain region is implicated in behaviors related to reproduction (32) and emotional process (83), it is possible that new cells proliferating here are involved in reproductive behaviors and emotional processing. Further studies may be required to test these speculations.

Hippocampus

The hippocampus is a bilateral structure in the brain that is responsible for formation of memory and emotion. Adult neurogenesis in the hippocampus was discovered in different animals, ranging from rodents (37) to humans (70). New neurons are generated at the subgranular zone (SGZ) of the hippocampus, which is an approximately two-cell-thick region. After cell proliferation, progenitors migrate through a short distance towards the granule cell layer. Maturation takes place during the migration process. To establish functional network, new cells project to the cornus am-monis (CA) 3 region and make synaptic connections with neurons there. The process of axonal growth and synaptic connect is rapid, which takes about 4 days to occur (42). It was shown that the new granule cells are morphologically and functionally identical to the mature neurons (54).

Neural stem cells of the hippocampus locate in the SGZ. Being similar to the olfactory mucosa and SVZ, three types of neural precursor cells could be found in the hippocampus (35): a) radial glia-like neural stem cells, which are termed as type 1 cells in the hippocampus; b) transiently amplifying cells, which are termed type 2 cells; and c) immature neurons (type 3 cells), which are migrating cells with DCX expression. In other words, the stem cell niches found in the hippocampus are similar to that in the SVZ: type 1 cells have properties of astrocytes and are able to undergo self-renewal, providing a source of multipotent stem cells in the hippocampus (91). Type 2 cells are the rapidly dividing cells, which are similar to type C cells in the SVZ. A subpopulation of type 2 cells and type 3 cells express DCX and these cells function as the neural substrate for circuit establishment. The new neurons will be recruited for functioning or they will die (56).

Neurogenesis in the hippocampus has been studied extensively, partly due to its role in memory formation and the fact that neurogenesis could be alternated by various manipulations, including behavioral/physiological (e.g., stress, aging, and learning) and pharmacological measures (e.g., psychotropic drugs) (56). One of the physiological factors that negatively affects neurogenesis is aging (58). The mechanism of how aging has effects is multifactorial: depletion of stem cell population, change of cell properties, or change in molecular factors may be the underlying factors. Corticosteroids, which are known as stress hormone, also are a negative regulator of neurogenesis (38). When adrenal glands (production organ of corticosteroids) of rats were removed, hippocampal neurogenesis increased. Chemically or electrically induced seizures could increase neurogenesis and contribute to aberrant network reorganization. New cells generated due to such manipulation, however, migrate to etopic locations in the hilus and form aberrant connections with neurons in the molecular layer. It is hypothesized that such abnormal formation of connections may be the cause of hippocampal kindling (86). In terms of behaviors, animals that live in an environment filled with chances of exploration (environmental enrichment) or are allowed exercise have more new cells (55). Learning tasks also show the ability to increase hippocampal neurogenesis (37). In short, physical and social treatment modalities may be beneficial for functioning of the hippocampus and further understanding may render opportunities for patients suffering from hippocampal lesions.

Functional Integration of New Neurons and Significance of Neurogenesis

Functional integration of newly generated neurons requires synaptic connections with the existing circuit. Several studies showed that DCX-expressing cells (i.e., new neurons) in the dentate gyrus receive synaptic input (4). These findings suggest that the new cells are not isolated from the existing circuit and receive input from other neurons. Furthermore, van Praag and coworkers (105) have assessed the physiological characterization of the new granule neurons in the hippocampus. It is shown that after approximately 7 weeks, the new cells display similar electrophysiological feature to the older dentate gyrus neurons. This provides further evidence that the new cells are likely to integrate into the network after maturation.

Another methodology to prove functional integration of new cells makes use of retrograde labeling (100). When a dye, such as Fluorogold, or other chemicals, which can be visualized after tissue processing, is injected into a target area in the CNS, neurons with axons projecting to this area uptake the dye. Then the dye will be transported from the axonal terminal to the cell body and accumulated. After sacrifice of the animal and sectioning, the fluorescent signal could be observed in the cell body of these neurons and thus it could be concluded that they are connected to the target area.

To confirm that the newborn cells in the hippocampus are integrated into the circuit and their axons make synaptic connections with the target area, injection of BrdU combined with retrograde labeling was used (42). At the beginning the new cells were labeled by BrdU injection. Several days later a retrograde labeling dye was injected in CA3 region of the hippocampus, which is the target projecting area of the mature neurons in the dentate gyrus. It is found that the BrdU-labeled new cells took up the dye quickly (within days). These cells also express DCX, indicating that they are early postmitotic progenitors in the dentate gyrus. Thus, this provides an additional piece of evidence that the newly generated cells make functional connections with the neuronal circuit in the hippocampus.

Another important issue is the functional influence of neurogenesis on animal behavior. One of the most direct ways to test what types of behaviors are affected by neurogenesis is by blocking neurogenesis in vivo. The most commonly used methods for blocking neurogenesis are irradiation and toxin treatment. In the 1970s, it was found that irradiation could decrease the cell proliferation in the dentate gyrus and the discriminative learning of these rats was depleted by the manipulation (8). More recently, Shors and coworkers (94) utilized a cytostatic compound methylazoxymethanol acetate (MAM) to deplete neurogenesis. By systemic injection into mice, this cytostatic compound will methylate DNA when cells are undergoing division and the cells taking up this drug will die. Thus, MAM was able to prevent cell cycle completion by killing the transiently proliferative cells in the hippocampus. In this study, a hippocampus-dependent task termed trace conditioning was assessed. During trace conditioning, a conditioned stimulus (tone) was presented to the animal first and, 500 ms after the stimulus termination, an unconditioned stimulus (electric shock) would be presented. If the stimuli were paired the animal showed an eye blink reaction. In contrast to the trace conditioning, delay conditioning presents both conditioned and unconditioned stimuli at an overlapping time and such a task is hippocampal independent.

When MAM was used to treat the animals, it is found that trace conditioning, but not delay conditioning, was interrupted and no eye blink response was found. Thus, from this study it is suggested that hippocampal neurogenesis was required for proper demonstration of trace conditioning, a hippocampal-dependent task. However, criticism rose against the use of MAM as the agent for blocking neurogenesis, such as affecting haematopoietic stem cell proliferation outside the CNS. On the other hand, discrepancy could be found among studies exploring the relationship between behaviors and neurogenesis. For instance, the effect of MAM on spatial memory formation is ambiguous and no definite conclusion could be made regarding the causal relationship (95).

Another emerging viewpoint related to neurogenesis is that neurogenesis may be the underlying cause of psychiatric disorders, including depressive disorder and schizophrenia (29). This idea provoked another view of neurogenesis: neural stem cells in adult brain are not only related to behavior but also exert more prevalent influence on cognitive functioning. For instance, sensorimotor gating deficit, which is a potential marker of schizophrenia, was found when hippocampal neurogenesis was blocked (62). Malberg et al. (71) discovered that antidepressants could increase hippocampal neurogenesis and other research groups showed that antipsychotics also showed the neurogenesis-promoting effect (68). These findings suggest an alternate explanation of the working mechanisms of antidepressants and antipsychotics. In the case of antidepressants, the therapeutic effect will not be demonstrated in clinical conditions until after treatment for 2 weeks (85). Because neurogenesis-promoting effect appears after the approximate period, it is hypothesized that the effect of antidepressants on neurogenesis is the underlying mechanism for the treatment. Furthermore, Santarelli et al. have shown that when hippocampal neurogenesis was blocked by irradiation, anxiolytic effect of antidepressant was abolished (88). As antidepressant could reduce the anxiety in a novelty-suppressed feeding test, the anxiolytic effect was abolished in irradiated rats (Fig. 1). Comparing to the study using MAM, irradiation caused restricted blocking of stem cell proliferation in the CNS rather than systemic influence. Nevertheless, changes in the microenvironment caused by irradiation are still possible. Although the current methodology may have side effects that could be confronting to data interpretation, these results provide a hint for the involvement of neurogenesis in behavioral and cognition functions.

Figure 1.

Ablation of neurogenesis by irradiation abolishes the anxiolytic effect of antidepressants. In nonirradiated mice, antidepressant treatment reduces anxiety and facilitates exploration in illuminated areas. In contrast, blockage of neurogenesis by irradiation prevents the anxiolytic effect of antidepressants.

Sexual Behavior and the Olfactory System

Chemical senses, which include olfaction and gestation, by no means are the major communication methods in humans when considering vision, audition, and even tactile sensation. Olfaction, however, is shown to play important roles behind the scenes and trigger behaviors in an unconscious manner. In humans, menstrual cycles could alter olfaction sensitivity (51) and influence social behaviors and emotions like attraction or disgust (25). More direct evidence was provided by rodent experiment, such as exposure to a strange male mouse after mating could block the fertilization of a female mouse (15). Although information gained from rodents may not be directly applied to humans, such data disclose the importance of chemical senses on social interaction and higher cognition of humans.

Although olfaction is one of the more “primitive” senses across the evolution process, humans, as a higher vertebrate, are still being affected by this chemosensation. A study conducted by Kaitz et al. (53) showed that newborns could identify mothers soon after birth and vice versa. In another study, human subjects could identify the emotional state (e.g., anxiety) of others by olfaction. A pheromone, which carries information across individuals, is a chemical sent by an individual and can elicit a specific pattern of behavior in another individual of the same species (23,59). The influence of pheromones could last for a relatively long period of time (e.g., months). Being different from odor, pheromone perception is not always perceived consciously. Pheromones could be found in secretions and body fluids like sweat, urine, and secretion from the pubic organs.

Pheromones are known to play an important role in reproductive functions. A well-illustrated study about the effect of pheromones on human menstrual cycle was reported by McClintok (72). In this study, it was observed that the menstrual cycle of female students living in a common apartment as roommates had their menstrual cycles synchronized. Furthermore, the cycle length was affected by the number of times exposed to males: more frequent exposure to males brought a shorter cycle length. It was viewed that this is related to the chance of fertilization. Exposure to compounds collected from armpits of female in the follicular phase of menstrual cycle to other females stimulates the ovulation and this implies that pheromones may come from this region.

Rodents copulate in a manner that can be analyzed easily. This makes the sexual behaviors in mice, rats, and hamsters useful for sexual performance analysis (60). A typical pattern of mating behavior was reviewed by Larsson and Ahlenius (60). When an experienced male rat is exposed to a sexually receptive female, three types of actions may occur: 1) mounting without penile penetration; 2) intromission, with penile insertion to the vagina; and 3) ejaculation, which appears as a long intromission with slow dismount. The mating process starts with mounting or intromission and, following several intromissions, eventually ejaculation will be triggered. Then the rat will remain sexually unresponsive to the female for several minutes, which is termed as postejaculatory interval. Copulation resumes after the refractory period and the same process repeats for 3—4 times until sexual satiety is achieved in the male rat.

To determine which brain regions are involved in the control of mating behavior, Heimer and Larssoon carried out a series of experiment using stereotaxic lesion method (44,45). One of their early findings is that when a junction connecting diencephalons and mesencephalon was damaged, the male rat became hypersexual (44)—ejaculation was achieved after a few intromissions and the postejaculatory period was greatly shortened. Although the exact location of damage exerted was not identified precisely, it was shown that brain circuit was involved in the control of sexual behaviors. Another study found that when the medial preoptic area (MPOA) was lesioned, sexual behavior was impaired or even abolished permanently (45). This finding suggested that brain circuit was involved in mating behavior from another viewpoint: motoric response of the male is mediated by MPOA. Thus, not only is the inhibitory part of mating mediated by neural circuits, the arousal and active part of it is also mediated by the CNS.

The MPOA has extensive fiber connection to the hypothalamus (60) and is likely to be influenced by nerve stimulation from hypothalamic regions. The stimulation is supposed to come from somatic and visceral sensory structures of the brain stem, which includes amygdaloid complex and hippocampus. Also, olfactory structures including olfactory tubercle and lobes send fibers to the MPOA and may influence its activation. Among these innervations, a particularly important one is the connection between MPOA and stria terminalis (1), which is a fiber system receiving projection from the amygdala. The amygdala, which in turns receives input directly from the olfactory system, may play an important role in the mating behavior.

As olfaction/pheromone perception is a major regulator of mating behavior, studies about the role of the olfactory system on mating have been carried out extensively. One of the studies has shown that when olfactory tract (structure connecting the olfactory bulb and amygdala) was cut, sexual behavior was impaired (46). Destruction of the main olfactory bulb also demonstrated sexual inhibition. One of the unexpected findings from these studies was that experience plays an important role in sexual behavior: experienced rats were able to copulate even after lesion on the olfactory system, while sexually naive rats were prone to not copulate after the lesion (106). Thus, it is clear that sexual experience (or olfactory memory) also plays a role in mating and the olfactory/pheromone cues may be important for mating for sexually naive animals.

From the studies mentioned above there is a pathway regulating sexual behavior. Olfactory stimulation and pheromones activate olfactory sensory neurons in the nasal cavity and the nerve impulse is sent to the olfactory bulb. The impulse from the olfactory bulb is then received by afferent fibers of neurons in the cortical and medial nucleus of the amygdala (89). The efferent fibers from the amygdala in turn stimulate neurons in the bed nucleus of the stria terminalis (BNST) and MPOA neurons are eventually activated. As the MPOA is an essential region for the motoric aspect of mating behavior, destruction of this site brings irreversible sexual inhibition in sexually naive rats. In summary, the olfactory system is a major neural regulatory system of mating behavior.

Interplay between Neurogenesis and Reproduction

Regulation of Neurogenesis by Pheromones, Mating Behavior, and Sex Hormones

Adult neurogenesis is subjected to regulation by different internal (e.g., growth factors, neurotransmitters, and hormones) and external (e.g., enriched environment, sensory inputs, temperature) factors (16). As a pheromone is released to the environment and induces behavioral changes of other individuals, it was classified as an environmental cue to animals. Increasing evidence shows the effect of pheromones on regulation of adult neurogenesis, which may in turn influence sexual behaviors in different species.

17α,20β-Dihydroxy-4-pregnen-3-one (17,20β-P) and prostaglandin F_2α (PGF_2α) are fish reproductive hormones and pheromones when released to surrounding environment. When they are released by female fish in water, 17,20β-P stimulates male arousal behaviors and milt (sperm and seminal fluid) production while PGF_2α induces male spawning behavior (99). After exposure to these two water-borne pheromones, neurogenesis in the brain of male goldfish was shown to increase (23). Interestingly, the increased neurogenesis is not only limited to diencephalons (where it is known to be involved in reproduction), but also could be found in other brain regions such as the cerebellum and several brain stem motor nuclei. The newborn neurons in the regions related to motor area are supposed to reorganize the structures and circuit, which may in turn affect spawning behavior. Although the detailed mechanism is unclear yet, these findings establish a linkage between specific pheromones and adult neurogenesis in reproductive behaviors of goldfish.

Adult neurogenesis could be found in avian telencephalon (82). The rate of neuronal turnover in the songbird high vocal center (HVC), a telencephalic nuclei participating in song learning, is associated with seasonal changes. Testosterone, on the other hand, promotes immature neuron production in the HVC. The ring dove is suggested as a model to study the significance of neurogenesis in bird courtship behavior (18). Ventramedial nuclei of the thalamus in the ring dove is essential for display of courtship behavior. When this area is lesioned, neurogenesis will be induced (65) and this is associated with the functional recovery of courtship. Co-housing with a mate promotes both neurogenesis in this area and the recovery of courtship vocalization (18). These studies suggest the association between adult neurogenesis and bird reproductive behaviors from different views: neurogenesis that occurs at physiological condition is required for learning and memorization of songs for courtship, and newborn neurons after lesions are necessary for recovery of courtship vocalization. Additionally, provision of social cues would improve neurogenesis and recovery process.

Unlike avian and teleost brain, adult neurogenesis is mainly restricted in the SVZ and hippocampus in mammals. Due to the close relation between the olfactory system and reproduction, studies that aimed to explore the relationship between neurogenesis and sexual behavior focused on SVZ and olfactory bulb neurogenesis. Prairie voles are monogamous and form life-long bonding with a mate (111). Female prairie voles remain sexually immature until they encounter an unfamiliar adult male vole. The onset of behavioral estrus and sexual receptivity is rapid, which requires 24—48 h of exposure to a male. A study conducted by Smith et al. (97) investigated the rate of SVZ neurogenesis in female voles upon exposure to an unfamiliar male vole, and it showed that the exposure increased the SVZ neurogenesis rapidly and robustly (with more than 90% increase). Elimination of circulating estrogen by ovariectomy blocked the effect of male exposure, while exogenous estrogen application restored the increase of neurogenesis. Considering the neurogenesis-promoting effect of estrogen (101), it is likely that pheromone exposure increases neurogenesis via estrogen. As immature neurons in the RMS did not express estrogen receptors (47), the hormone may affect neurogenesis through other intermediate molecules. Estrogen could upregulate expression of various neurotrophic factors including BDNF, nerve growth factor, and other neurotrophins (98), which may consequently affect neurogenesis. The suggested molecular mechanism of neurogenesis regulation will be discussed later in this review.

Being similar to the prairie vole, female sheep only become fertile when they are exposed to unfamiliar rams. Recently, an interesting study reported that after exposure to novel rams, the number of dividing neurons in the hippocampus of female sheep increased robustly (43), which is accompanied with a sharp increase in circulating luteinizing hormone. These changes occurred rapidly (within minutes to 2 days), which echoes with the change of female sheep reproductive state: exposure to unfamiliar male rams induces fertility of females within minutes (43). In contrast to studies using rodents as models (59), prolactin was not increased after exposure to the opposite sex. The findings illustrated: 1) pheromone exposure increases hippocampal neurogenesis and 2) the molecular regulations of neurogenesis in rodents and ungulate are different. Due to lack of information in ungulate neurogenesis, several questions remain elusive to further confirm the roles of newborn neurons in ungulate reproduction. How long does a new neuron in ungulate brain become mature and integrate into the existing neural circuit? Is neurogenesis in the olfactory system and SVZ affected by exposure to pheromones? Is neurogenesis affected by familiar, rather than unfamiliar, male rams? Is there a causal relationship between the increased neurogenesis and endocrinal changes, or are they associated events? Because most information on neurogenesis comes from rodents, further investigation on ungulate neurogenesis may shed light on reproductive significance of neurogenesis across species.

Studies using rodents like mice and rats revealed the regulatory function of prolactin on neurogenesis (59,69, 93). Prolactin, a hormone acting in the brain, mediates onset of maternal behaviors in rodents like pup retrieval and crouching over the pups (14). A pioneering study conducted by Shingo and coworkers investigated the effect of copulation on prolactin expression and SVZ and olfactory bulb neurogenesis (93). When comparing to age-matched virgin controls, pregnant mice showed 65% more SVZ proliferative cells. The neurogenic effect was also found in pseudopregnant females (i.e., those mated with castrated male mice). This implies the mating action alone would induce the increased neurogenesis. Prolactin (which is upregulated during pregnancy) infusion reproduced the same neurogenic effect as pregnancy (59,93). Not surprisingly, partly knockout of prolactin receptor reduced the neurogenic effect of copulation by half (93). According to Larsen et al., SVZ neurogenesis was also promoted when virgin female mice were exposed to male mice, without physical contact, or to male urine (59). The increase of neurogenesis was also associated with an increase in serum prolactin level. These findings suggest the importance of pheromone and mating in promoting SVZ neurogenesis, which is similar to other species mentioned above. Furthermore, it was shown in Larsen et al.'s study that the olfactory bulb neurogenesis was also increased after the pheromone exposure, which implies functional significance of neurogenesis in olfactory processing. Similar findings were reported by Mak et al. (69), who showed that exposure to male mice soiled bedding increased SVZ neurogenesis and the prolactin level. Additionally, luteinizing hormone level and hippocampal neurogenesis were also upregulated by the soiled bedding. With the use of prolactin and leutinizing hormone receptor knockout mice, it was confirmed that the hippocampal neurogenesis is due to the increase of the luteinizing hormone but not prolactin; in contrast, prolactin is the regulatory factor of SVZ neurogenesis (69).

Newborn neuroblasts in the SVZ migrate to the olfactory bulb and a specialized region located at the posterior dorsal portion of the olfactory bulb, termed accessory olfactory bulb (AOB) (10). The AOB resembles the olfactory bulb anatomically, which shows different laminar layers. The AOB belongs to part of the vomero-nasal system, which is suggested to process pheromone signals (11). Sensory receptor neurons with pheromone receptor expression are located within the nasal cavity and connected to the AOB. Recently, it was shown that a portion of the neuroblasts originated from the SVZ became mature and displayed typical features of functional interneurons in the AOB. Furthermore, exposure of female mice to male-soiled bedding promotes the survival of the new neurons in the integration process. This finding indicates that cell survival in the AOB could be promoted by sociosexual cues, which is analogous to the study of Alonso and coworkers: olfactory discrimination learning promotes survival of olfactory neurons (2). These studies suggest that the increase in SVZ neurogenesis not only regulates newborn neurons in the olfactory bulb, but also has influence on neural circuit remodeling in the AOB. Further studies will be required to determine the roles of AOB neurogenesis in rodent reproductive behavior.

Apart from the SVZ, there are studies investigating whether other regions are involved in neurogenesis (5). For instance, neurogenesis in the posterior medial amygdala (MeP) and medial preoptic area (MPOA) was assessed after testosterone injection and mating (5). Being different from the SVZ and the olfactory bulb, no difference in neurogenesis (including both cell proliferation and survival) could be found in animals after mating, while testosterone only increased cell proliferation in the MeP but not the MPOA. This indicates that neurogenesis in these regions is unlikely to be regulated by reproductive behavior or related stimuli.

Molecular mechanisms of neurogenesis are undergoing intensive research, and various trophic factors, molecules, and hormones are shown to be involved in this process. For instance, BDNF is known to upregulate neurogenesis (87). As mentioned above, adrenalectomy decreases the level of steroids and increases neurogenesis and this suggests that steroid hormones are tightly linked to neurogenesis (38,63). Serotonin, a neurotransmitter widely found in the CNS, positively regulates neurogenesis (13). Drugs that promote serotonin content at synaptic junctions are also found to increase neurogenesis (71).

Several signaling pathways have been hypothesized to regulate adult neurogenesis. One of them is the the adenylyl cyclase—cAMP—PKA pathway, which is activated by neurotransmitters serotonin and noradrenalin (70). After serotonin/noradrenalin binding to corresponding receptors, the receptor-coupled heterotrimeric G proteins are activated. Adenylyl cyclase is in turn activated by G proteins and cAMP is produced. cAMP then activates cAMP-dependent protein kinase (PKA), and target proteins are phosphorylated. (74). The PKA activation could also be observed in animals treated with different classes of antidepressants, like selective serotonin reuptake inhibitors (SSRIs), imipramine, tranylcypromine, and electroconvulsive seizure (ECS) (78). The common targeting of PKA from different antidepressants suggests that PKA activation is a required step for the treatment efficacy of antidepressants.

Apart from the adenylyl cyclase—cAMP—PKA pathway, another potential pathway is the phospholipase c pathway (103). Activation of α1-adrenoceptors activates PLC, which in turn leads to intracellular mobilization of calcium ions and subsequently Ca²⁺-calmodulin-depen-dent kinase. The target proteins are activated by this kinasae and bring physiological effects. Another pathway, Rasmitogen-activated protein (MAP) kinase kinase (MEK)-extracellular signal-regulated protein kinase (ERK) pathway, is one supposed to be activated by antidepressants (108).

The activation of protein kinase (PKA, Ca²⁺-calmodulin-dependent kinase, ERK) functions as phosphorylation of target proteins, which brings about their activation. One of the well-studied common target protein activated by these pathways is the cAMP response element binding protein (CREB; pCREB as the phosphorylated form) (52). Protein kinases catalyze the phosphate group from ARP to serine (an amino acid) residues to CREB. pCREB then initiates gene transcription by recruiting other cofactors and triggers cellular and behavioral response, such as neurogenesis (109). In short, CREB is likely to be the common target of different classes of antidepressants and the activation of CREB may be the key to regulation of neurogenesis.

Being similar to CREB, BDNF is another molecule speculated to be involved in the regulation of neurogenesis (90). Neurotrophic factors are proteins affecting the growth and functioning of the CNS and are usually regarded to be beneficial for cell survival, differentiation, and neural plasticity. Neurogenesis is also increased after BDNF treatment (84) and it is a target downstream to pCREB. For example, BDNF transcript/mRNA in the cortex and hippocampus increased after antidepressant treatment or electroconvulsive seizure (80). In contrast, when animals were subjected to stressful situations that decreased neurogenesis, BDNF level decreased and antidepressants could reverse the change (73). Although conflicting results regarding BDNF level after antidepressant treatment exist among studies, the methodology, stress, and handling of animals may be confounding factors to the interpretations of result (70).

BDNF binds to tyrosine kinase B (trkB) receptors in the brain and activates various pathways, including the MEK—REK pathway. BDNF expression was regulated by CREB because the promoter region of BDNF has a CRE element, which could be bound to CREB (102). Because pCREB level is increased by antidepressant treatment, it is likely that BDNF expression is also regulated by the antidepressants through pCREB. In mice with CREB deficiency, the upregulation effect of BDNF by antidepressants was blocked and this supports the relationship between CREB and BDNF expression (9).

The precise roles of pCREB and BDNF in neurogenesis are still undergoing investigation. One of their proposed functions is promoting the survival of immature neurons (77). At the first 2 weeks after proliferation, pCREB is expressed in the immature neurons. After that period pCREB will decrease and apoptosis rate increases simultaneously (34). So the phosphorylation of CREB may promote the survival rate of immature neurons to ensure their maturation into neurons. Transgenic animal study of mice with decreased BDNF expression showed that the survival rate of newborn neurons in the mice was significantly lower than wild-type counterpart (87), which also suggests the prosurvival function of BDNF in neurogenesis.

Taken together, there is an increasing number of internal and external factors found to affect neurogenesis, and the exploration of effect of sex hormones and pheromones may not only shed light on understanding of neurogenesis mechanisms but also provide insight to disorders that are related to reproductive functions.

Roles of Newborn Cells in Mating Behavior

Although the evidence showing the association among reproductive behavior, pheromones, and neurogenesis is mounting, the precise roles of newborn neurons in sexual behavior are still under debate (43,97). In a prairie vole study it is suggested that the generation of new cells in the SVZ and RMS is involved in pair bond formation (97). This hypothesis is based on two findings: 1) prairie voles are monogamous and 2) olfactory bulb removal inhibits the estrus induction and mate preference (107). However, due to the pervasive influence of olfactory bulb removal and lack of studies about consequences after neurogenesis inhibition, the function of the new neuron formation in prairie voles remains elusive.

As mentioned earlier, the blockade of neurogenesis provides an effective measure to test whether neurogenesis is an essential criterion for a specific behavior or physiological change. The ventromedial nucleus (VMN) of the ring dove is a region that mediates courtship, and no neurogenesis occurs in physiological condition (18). However, neurogenesis occurs after a lesion is exerted in this area. The neurogenesis is associated with recovery of courtship behaviors (18). When the neurogenesis is blocked by Ara-c infusion, recovery is hampered (19). This establishes the causal relationship between neurogenesis and postlesion recovery: newborn neurons are required for behavioral recovery. However, due to lack of neurogenesis in the VMN in physiological condition, it is unlikely that neurogenesis is required for courtship behavior normally. Also, Ara-c infusion in the brain may affect other brain regions, so the effect of Ara-c may be exerted via suppression of neurogenesis of other regions.

A study conducted by Huang and Bittman (49) demonstrated the participation of adult-born neurons in copulation. The study utilized c-fos, an immediate early gene product expressed in stimulated neurons, to determine whether newborn neurons are stimulated by sexual stimulus. All 7-week-old neurons, originated from the SVZ, were found migrated into different layers of the olfactory bulb. When an animal was subjected to copulation just before sacrifice, about 30% of these neurons were found to express c-fos. The proportion of c-fos-expressing cells is significantly higher in animals being presented with sexual cues (either an estrous female or female-soiled bedding). This suggests that the new cells integrated into the neural circuit responsible for copulation several weeks after birth, and they may play a significant role in mediating the responsiveness to sexual cues. In contrast, no new cells in the BNST, medial amygdale, or MPOA express c-fos after sexual cues presentation, which means neurogenesis in these regions might not play a significant role in copulation. Due to lack of suitable method to block neurogenesis at that time, how neurogenesis affects copulation remains to be determined (49).

Utilizing intracerebroventricular infusion of Ara-c, Mak et al. disclosed the potential causal relationship between adult SVZ neurogenesis and female mice sexual behavior (69). When female mice were exposed to a dominant male, both SVZ and hippocampal neurogenesis was increased. This was accompanied by the preference to chemosensory investigate dominant mice rather than subordinate ones. When neurogenesis was blocked by Ara-c infusion, both the pheromone-induced neurogenesis and mate preference were abolished. This established the causal relationship between neurogenesis and mate preference. It is possible that the pheromone from the dominant male exerted endocrinal and structural changes in the female olfactory system, which is associated with copulation. The changes may bring alternated olfactory discrimination or formation of olfactory memory (30). However, because Ara-c suppresses neurogenesis in both the SVZ and hippocampus simultaneously, it is possible that the suppressed mate preference is due to the influence on the hippocampus. Further studies that could differentially suppress SVZ and hippocampal neurogenesis will be helpful to distinguish their different effect on behaviors. This study provides evidence that neurogenesis plays an important role in female mate selection, while another study showed that suppressed neurogenesis was associated with decreased sexual performance and olfactory pathway activation (61). It is likely that newborn neurons are important for reproduction in both sexes, and further confirmatory studies are needed.

Neurogenesis and Maternal Behavior

Involvement of neurogenesis in reproductive behavior is also shown in maternal behavior. In the study of Shingo et al. (93), the physiological significance of increased olfactory bulb neurogenesis was attributed to preparing for maternal adaptation. Olfactory discrimination and formation of new odor memory are important in caring for young (36), because offspring recognition and associated maternal behavior may depend on the remodeling of the olfactory system circuit (12). It was later shown that exposure to male mice facilitated the advancement of female mice maternal behavior (59). Although virgin females develop full maternal behaviors (e.g., pup retrieval to the nesting position and crouching over the pups) after exposure to the pups after 21 days, exposure to male pheromone significantly accelerated the behavioral development. The advanced behavior was associated with an increase in SVZ and olfactory bulb neurogenesis. Considering the time for maturation of new neurons, and development of maternal behavior and pregnancy, an interesting correlation could be found. New neurons take 2—3 weeks for maturation and integration into existing circuits (66), while both development of maternal behavior and pregnancy in rats take 21 days. It is hypothesized that the exposure to male pheromones during copulation might facilitate changes in maternal behavior and olfaction during pregnancy, which is prepared for the future caring of pups (93). This hypothesis is supported by a study conducted in adult zebra finch, which showed a peak of neurogenesis in parent zebra finchs' nidopallium caudale (NC) when their juvenile reached fledging (a stage that still needs parental care) (6). When the juveniles reached independence, a significant decrease was found in the parent's NC. A positive correlation between number of newborn neurons and fledgling juveniles was found, which suggests that the neurogenesis may participate in caring for young.

Conclusion

The findings reviewed in this article illustrated the interplay among sexual cues, reproduction, and neurogenesis. Although the studies in this field have just emerged, increasing evidence supports the relationship between reproductive function and adult-born neurons. Experiment from different species demonstrated the regulatory effects of pheromones and sexual interaction on brain neurogenesis; however, the functional significance of new neurons in reproduction needs to be further clarified. For instance, is neurogenesis in male animals important for their reproductive functions? Apart from mate preference and maternal behaviors, are newborn neurons important for other aspects of sexual behaviors, like libido and copulatory performance? Is neurogenesis in other brain regions, like the amygdala and hypothalamus, involved in sexual behaviors? To understand the precise roles of newborn neurons in reproduction, further studies are required. Such understanding may provide new insight to sexual dysfunction and medicine, in which brain plasticity may be shown to involve in normal sexual functioning or sexual disorders. The studies in this field will be a great challenge in the future, but the results may bring revolutionary views on the importance of brain plasticity and sexual medicine.

Footnotes

Acknowledgments

This study was supported by funding from the Jessie Ho Professorship in Neuroscience (The University of Hong Kong Foundation for Educational Development and Research Limited), and the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (Project No. AoE/B-15/01-II).

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Reproduction: A New Venue for Studying Function of Adult Neurogenesis? 1

Abstract

Keywords

Introduction

Adult Neurogenesis in the Brain

Neurogenesis in Specific Regions

Olfactory System

Olfactory Epithelium/Mucosa

Subventricular Zone and Olfactory Bulb

Amygdala

Hippocampus

Functional Integration of New Neurons and Significance of Neurogenesis

Sexual Behavior and the Olfactory System

Interplay between Neurogenesis and Reproduction

Regulation of Neurogenesis by Pheromones, Mating Behavior, and Sex Hormones

Roles of Newborn Cells in Mating Behavior

Neurogenesis and Maternal Behavior

Conclusion

Footnotes

Acknowledgments

References