Abstract
The hippocampus is a part of the limbic system found in the temporal lobe. Hippocampal neurogenesis, the ability of the hippocampus to generate/produce new neurons all through to adulthood, has been linked to emotion moderation, spatial navigation, learning, memory, and cognitive function. These functions are usually impaired in depression and anxiety and hence the speculations that hippocampal neurogenesis plays a critical role in the etiology, pathophysiology and even the treatment depression and anxiety. The hippocampal neurogenesis hypothesis attempts to explain the role of hippocampal neurogenesis in the development of depression and anxiety based on findings from various studies. Findings that neurogenesis is involved in regulation of emotions, cognitive functions, memory and learning were important in affirming the hypothesis. Other studies established decreased hippocampal volume, function and neurogenesis in depressed subjects compared to controls. Studies involving treatment with some antidepressants revealed that they restore the hippocampal volume and neurogenesis. However, it is not clear whether hippocampal neurogenesis plays a role in anxiety because there are conflicting findings with regard to the relationship between hippocampal neurogenesis and anxiety. In addition, there is enormous evidence that hippocampal neurogenesis interacts with genetic, epigenetic and environmental factors in the etiology of depression and thus neurogenesis alone does not predict depression. However, the actual role of hippocampal neurogenesis in depression and anxiety remains unclear. This paper will evaluate different studies to establish the involvement of hippocampal neurogenesis in anxiety and depression.
- Introduction
The hippocampus is a part of the limbic system found in the temporal lobe. The limbic system is implicated in functions such as emotion moderation, spatial navigation, learning and memory and cognitive function (Onksen, 2011; Mu & Gage, 2011; ; Snyder & Cameron, 2011; Ransome, Renoir, & Hannan, 2012; Jun, Hussaini, Rigby, & Jang, 2012). More specifically the ability of the hippocampus to generate/produce new neurons all through to adulthood has been linked to these functions. The said ability is referred to as hippocampal neurogenesis and it is a unique property that is only shared with the olfactory bulb. There is significant evidence that hippocampal neurogenesis plays a critical role in the etiology, pathophysiology and even the treatment of some mental disorders (psychiatric, moody and neurodegenerative disorders) such as depression, anxiety, schizophrenia, Huntington disease, Alzheimer’s disease and even in drug addiction (Sahay & Hen, 2007; Onksen, 2011; Mu & Gage, 2011; Jun, Hussaini, Rigby, & Jang, 2012).
The hippocampal neurogenesis hypothesis is premised on several interrelated factors. The first premise has to do with the role of hippocampus in cognitive functions and mood moderation, all of which are significantly impaired in depressed subjects. Secondly, there are the structural and functional changes in the hippocampus of depressed subjects (from imaging, mice studies and virtual-reality spatial memory navigation tasks studies). The third premise is the reduced neurogenesis associated with stress (one of the factors that often predict depression), the fourth premise is the effect of antidepressants, and other alternative intervention strategies employed in treatment of depression. However, there are conflicting findings with regard to the relationship between hippocampal neurogenesis and anxiety. In addition, there is enormous evidence that factors other than hippocampal neurogenesis play a vital role in depression and thus neurogenesis alone does not predict depression (Sahay & Hen, 2007; Onksen, 2011). This paper will particularly evaluate the evidence of the involvement of hippocampal neurogenesis in stress, anxiety and depression.
- The physiology of the hippocampus and the role in symptoms of depression
As earlier mentioned the hippocampus plays a critical role in the regulation of emotions, mood, cognitive function and spatial navigation. Some studies have shown that hippocampal neurogenesis is necessary functions. Studies with mice exposed to methylazoxymethanol (MAM) (a chemical that stop hippocampal neurogenesis) revealed that such mice had long-term cognitive, emotional impairments and behavioral deficits. The said deficits were identical to those observed in mice exposed to chronic stress. The cognitive and emotional disabilities were not observed immediately after stopping neurogenesis but four weeks after cessation of MAM treatment. This implies that continuous neurogenesis and complete integration of the new neurons into the appropriate circuits (which takes 4-6 weeks in rodents) is necessary for maintenance of cognitive and emotional balance (regulation) that is often lacking in depressed subjects. Suffice to say that the fact that the emotional, cognitive and behavioral deficits observed in this study resemble those observed in mice exposed to chronic stress is a clear indication that hippocampal neurogenesis plays a role in the pathophysiology of stress (Sahay & Hen, 2007; Krishnan & Nestler, 2008; Snyder & Cameron, 2011). As such, it can be inferred that cognitive, emotional and behavioral deficits observed in depression are linked to reduced adult hippocampal neurogenesis.
Some studies have established that hippocampal neurogenesis and astrogiogenesis play a role in the development and remission of symptoms of depression. These studies established that blocking of hippocampal neurogenesis causes the symptoms associated with depression and that spontaneous recovery (remission) correlates to continuous proliferation and incorporation of the new cells. The studies also established that antidepressants rely on their ability to restore hippocampal neurogenesis to reverse the cognitive and emotional deficits associated with depression. These findings agree with earlier findings that hippocampal neurogenesis is vital for the regulation of the emotional and cognitive functions that are impaired in depression (Sahay & Hen, 2007; Mateus-Pinheiro, et al., 2013). The study concluded that reduced neurogenesis interacts with other factors to produce depression symptoms and spontaneous (remission) and pharmacological recovery from the said symptoms depends on the restoration of neurogenesis.
Studies with mice in which hippocampal neurogenesis is blocked have revealed that some forms of learning require hippocampal neurogenesis. These mice also have deficits in fear conditioning, working and spatial memories. Another function of hippocampal neurogenesis that points to its involvement in depression is its influence on the functional and structural integrity of dentate gyrus. Studies have indicated that reduced hippocampal neurogenesis has a negative impact on the function and structure of the dentate gyrus which plays a role in the development of depression(Sahay & Hen, 2007). Histological studies of the dentate gyrus indicate that there is an increase in packing density of denate granule cells and a decreased soma size in depressed subjects (Sahay & Hen, 2007). However, there is need for more follow up studies on the relationship between hippocampal neurogenesis and the structure and function of dentate gyrus.
- Hippocampal volume and function in depression
One of the earliest findings that gave impetus to the hypothesis that decreased hippocampal neurogenesis is involved in the pathophysiology of depression and anxiety was obtained from magnetic resonance imaging (MRI) studies. Several MRI studies have constantly revealed a reduction in hippocampal volume in individuals with depression compared to controls (Videbech & Ravnkilde, 2004; Campbell, Marriott, Nahmias, & MacQueen, 2004; Sahay & Hen, 2007; Onksen, 2011). There is also evidence that the degree of the decrease in the hippocampal volume correlates with the incidences of depression and the length of time the depression remains untreated (Sahay & Hen, 2007). There is also evidence that reduced hippocampal volume is a risk factor for psychiatric conditions.
While there is no functional MRI study indicating dysfunction of the hippocampus, studies using virtual-reality spatial memory navigation tasks have revealed that depressed individuals perform poorly in these tasks compared to the controls (Gould, et al., 2007; Sahay & Hen, 2007; Cornwell, et al., 2010). Cornwell et al., (2010) found that the depressed subjects with impaired spatial memory navigation showed (by magnetoencephalography (MEG)) less activity in the parahipocampal cortices, left posterior hippocampus and the anterior hippocampus is a function of the hippocampus and thus the findings are indicative of hippocampal dysfunction. In addition, hippocampal dysfunction may affect the activity of other neural circuits in the nucleus accumbens, amygdale and the prefrontal cortex that interact with the hippocampus to modulate emotions. Several factors have been implicated in the alterations in the structure and function of the hippocampus observed in depression. Reduced neurogenesis is one of the factors that has been linked to the reduction in the size of the hippocampus observed in depression and stress.
- Depression, anxiety and adult hippocampal neurogenesis
While there are several hypotheses to explain the etiology and pathophysiology of depression, the hippocampal neurogenesis is the most widely accepted theory (Sahay & Hen, 2007). The main premise of this theory is the evidence from numerous studies that stress is a major factor contributing to the development of depression. In fact, some scholars believe that stress is a part of the continuum of depression (Dranovsky & Hen, 2006; Sahay & Hen, 2007; Onksen, 2011). Subsequent studies revealed that chronic stress reduce hippocampal neurogenesis. In addition, the regulation of the hypothalamic-pituitary axis, which regulates stress response, depends on hippocampal neurogenesis (Sahay & Hen, 2007). However, there are studies indicating depression can be mediated by stress without necessarily reducing hippocampal neurogenesis. In addition, some studies show that mice with blocked hippocampal neurogenesis are not particularly vulnerable to stress (Sahay & Hen, 2007). Additionally, activity in other brain regions has been implicated in the etiology and treatment of depression. Neurogenesis interacts with environmental and genetic factors in the etiology and pathophysiology of depression in animal models. While the said activity may be influenced by hippocampal neurogenesis, they imply that neurogenesis does not work independently to cause depression at all times (Sahay & Hen, 2007). The shortcoming of these findings is that they have not been replicated in human studies.
With regard to anxiety, it is not clear how neurogenesis is linked with neurogenesis because there are conflicting findings from different studies on the relationship. For instance, while some studies on the effect of exercise on anxiety in mice have shown that exercise increases anxiety, while others studies have shown that exercises decreases anxiety. This implies that the etiology of anxiety is mediated by complex interaction of various factors. In other words, some studies have established that there is no link between neurogenesis and anxiety, others show increased neurogenesis and others show reduced neurogenesis in mice with anxiety. However, it is vital to note that although these studies have not been replicated in humans but clearly implies that the pathophysiology of anxiety is more unclear than that of depression.
5.0 Antidepressants and hippocampal neurogenesis
In addition to the decreased hippocampal volume and function, the activity of many antidepressants has been a major pillar in the neurogenesis hypothesis that explains the pathophysiology of depression. There is evidence that antidepressants reverse the reduction in hippocampal volume observed in depressed patients. Numerous studies have revealed that chronic treatment with antidepressants and other non-pharmacological depression interventions have been found to stimulate adult neurogenesis (Dranovsky & Hen, 2006; Sahay & Hen, 2007; Jun, Hussaini, Rigby, & Jang, 2012). Laboratory studies have shown that some antidepressants recruit new neurons and the efficacy of some antidepressants such as fluoxetine, imipramine, tricyclic and cannabinoid HU210 requires hippocampal neurogenesis. It can be deduced from these studies that adult hippocampal neurogenesis is necessary in facilitating the antidepressants’ behavioral effects (Warner-Schmidt & Duman, 2006; Sahay & Hen, 2007; Surget, et al., 2008; Lucassen, et al., 2010; Onksen, 2011; Sahay, et al., 2011; Surget, et al., 2011; Jun, Hussaini, Rigby, & Jang, 2012). In fact, some Positron emission tomography imaging studies show that the hippocampus one of the neuronal substrates of antidepressants and thus the mode of action of the said antidepressants involves the hippocampal neurogenesis as a target (Sahay & Hen, 2007). As such, a better understanding of adult hippocampal neurogenesis will help in the development of more effective antidepressants.
Suffice to say, there are some antidepressants that act through neurogenesis-independent pathways (Sahay & Hen, 2007). Some of the antidepressant drugs with neurogenesis-independent mode of action include vasopressin 1b antagonist, CRF1 antagonist and MCHR1 antagonist. In addition, in mice x-ray irradiated to obstruct neurogenesis, some mood-enhancing intervention, though they increase hippocampal neurogenesis, have been shown to work in the absence of neurogenesis (Sahay & Hen, 2007; Onksen, 2011). These studies imply that the hippocampal neurogenesis is not the only factor that influences the etiology, pathophysiology and the treatment of depression (Sahay & Hen, 2007; Onksen, 2011).
5.0 Conclusion
The role of the hippocampus in the regulation of moods, emotions and cognitive functions led to extensive research on its role in depression and anxiety. The findings of these studies formed the basis of the hippocampal neurogenesis hypothesis. Some of the findings that support this hypothesis include reduced size and function of the hippocampus, reduced hippocampal neurogenesis in depression and restoration of hippocampal volume and neurogenesis by antidepressant. From the evaluation of various studies the actual role of hippocampal neurogenesis in depression and anxiety remains unclear. However, there are indications that hippocampal neurogenesis plays a role in the etiology, pathophysiology and treatment of depression; only that the exact role remains unclear. In addition, hippocampal neurogenesis does not act independently to produce the symptoms of depression but interacts with genetic, epigenetic and environmental factors. As such, reduced hippocampal neurogenesis by itself may not lead to depression. In other words, depression and anxiety follow pathways that are both dependent and independent of hippocampal neurogenesis
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