Review
Effects of diabetes on hippocampal neurogenesis: Links to cognition and depression

https://doi.org/10.1016/j.neubiorev.2013.03.010Get rights and content

Abstract

Diabetes often leads to a number of complications involving brain function, including cognitive decline and depression. In addition, depression is a risk factor for developing diabetes. A loss of hippocampal neuroplasticity, which impairs the ability of the brain to adapt and reorganize key behavioral and emotional functions, provides a framework for understanding this reciprocal relationship. The effects of diabetes on brain and behavioral functions in experimental models of type 1 and type 2 diabetes are reviewed, with a focus on the negative impact of impaired hippocampal neurogenesis, dendritic remodeling and increased apoptosis. Mechanisms shown to regulate neuroplasticity and behavior in diabetes models, including stress hormones, neurotransmitters, neurotrophins, inflammation and aging, are integrated within this framework. Pathological changes in hippocampal function can contribute to the brain symptoms of diabetes-associated complications by failing to regulate the hypothalamic-pituitary-axis, maintain learning and memory and govern emotional expression. Further characterization of alterations in neuroplasticity along with glycemic control will facilitate the development and evaluation of pharmacological interventions that could successfully prevent and/or reverse the detrimental effects of diabetes on brain and behavior.

Introduction

Diabetes is a chronic metabolic disorder characterized by abnormally high plasma glucose levels, also known as hyperglycemia. According to the World Health Organization (WHO, 2011), over 220 million people around the world have diabetes. In the United States, approximately 25.8 million children and adults have diabetes, a statistic that represents 8.3% of the population (ADA, 2011). Moreover, the number of people suffering from diabetes has been estimated to likely double by the year 2030 due to urbanization, obesity and aging (Wild et al., 2004).

Two main forms of diabetes exist in humans: diabetes mellitus type 1 (T1D) and diabetes mellitus type 2 (T2D). The two classifications differ based on the etiology of the hyperglycemia and the person's response to insulin. T1D, a disease characterized by insulin deficiency, results from autoimmune destruction of the insulin-producing pancreatic beta cells. With onset typically during childhood or early adulthood, T1D is fatal in the absence of insulin replacement therapy. T1D represents approximately 5–10% of all diagnosed cases of diabetes. T2D, on the other hand, accounts for 90–95% of cases (NDIC, 2011) and is characterized by decreased insulin sensitivity in peripheral tissues and resultant perturbation of insulin secretion. This derangement is commonly associated with other metabolic disturbances like hypercholesterolemia, hypertension, and obesity.

Diabetes can lead to a number of secondary complications affecting multiple organs in the body including the eyes, kidney, heart, and brain. The most common diabetic brain complications include cognitive decline and depression. The incidence of cognitive decline, measured by behavioral testing, may be as high as 40% in people with diabetes (Dejgaard et al., 1991), and as many as 39% of a sample of people with diabetes in one study indicated having a subjective feeling of cognitive decline (Brismar et al., 2007). A systematic review of longitudinal studies reported an overall 50–100% increase in the incidence of dementia in people with diabetes (Biessels et al., 2006). Two more recent meta-analyses also concluded that diabetes is associated with lower cognitive performance and increased risk for dementia (Gaudieri et al., 2008, Lu et al., 2009). A recent review reported impaired cognition with effect sizes of 0.3–0.8 SD units in people with T1D compared to non-diabetic controls and 0.25–0.5 SD units in people with T2D compared to non-diabetic controls (McCrimmon et al., 2012).

In addition to symptoms of cognitive decline, both T1D and T2D are associated with a higher prevalence of depression. A recent review reported that the prevalence of depression in T1D was 12% versus 3.2% in the non-diabetic population (range 5.8–43.3% versus 2.7–11.4%). Similarly, the prevalence of depression in T2D was 19.1% versus 10.7% in the general population (range 6.5–33% versus 3.8–19.4%) (Roy and Lloyd, 2012). The relationship between diabetes and depression is reciprocal as depression is also considered a risk factor for the development of diabetes (Renn et al., 2011). Comorbid depression and diabetes is associated with poor self-care, lack of exercise, and nonadherence to dietary or medication routines, leading to inadequate glycemic control. The treatment of depressive symptoms alone may produce benefits but, nevertheless, may not necessarily improve glycemic control (Petrak and Herpertz, 2009).

Although the mechanisms responsible for producing the high rates of depression and dementia in diabetes are not well understood, the overlap of numerous physiological and non-physiological factors likely account for the pathogenesis of their comorbidity (Ismail, 2010). Non-physiological factors, such as sedentary lifestyle, diet, lack of self-care and history of substance abuse, contribute to the development of diabetes. There is also an emotional burden related to managing diabetes that is stressful for many patients. Insulin resistance in the brain, in addition to the periphery, has emerged as a potential physiological link for T2D with both depression and dementia (Silva et al., 2012). Inadequate signaling from the absence of insulin may produce a similar set of physiological disturbances in T1D (Korczak et al., 2011). Diabetes and depression are also associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis (Champaneri et al., 2010). Whether HPA axis hyperactivity in diabetes might cause depression, or exacerbate certain depressive behaviors is unclear, but abnormal HPA responses have been proposed as a biomarker that is ameliorated by antidepressant treatment in patients that recover from depression (Ising et al., 2007). Likewise, increased inflammation has been associated with the pathogenesis of both diabetes and depression (Haroon et al., 2012, Osborn and Olefsky, 2012, Stuart and Baune, 2012). Diabetes, and the effects of insulin, have been associated with alterations of the same neurotransmitters (dopamine and serotonin), neurotrophins (brain derived neurotrophic factor (BDNF)) and cell signaling mechanisms (alpha serine-threonine protein kinase (Akt); insulin growth factor-1 (IGF-1)) that have been implicated in depression (Duman and Monteggia, 2006) and the effects of antidepressants (Hoshaw et al., 2005). Even though the common occurrence of depression and diabetes is expected from many overlapping predisposing physiological and non-physiological factors, it is still unclear which mechanisms are most important or which patients will develop comorbid complications.

Evidence from animal studies can help elucidate mechanisms responsible for depression in humans with diabetes leading to identifying biomarkers and new treatments. However, studying models of depression in animals differs greatly from studying clinical depression in humans. The diagnosis of depression in humans requires meeting DSMIV-TR criteria for depression, which includes subjective report of feeling sad and/or decreased interested in pleasurable activities. Animals, on the other hand, cannot be diagnosed with depression. Instead, scientists can only measure symptoms or behaviors that represent animal analogs from which they can infer similarity to symptoms of depression in humans.

The key to understanding the link between diabetes with cognitive deficits and mood disorders may lie in the process of neuroplasticity, or the structural remodeling of the brain after exposure to stress or disease. Prolonged exposure to stress has been shown to lead to a series of neuroplastic changes in brain regions that are especially sensitive to stress, such as the hippocampus. Structural remodeling engages neuroplasticity in response to environment, diet, immune and endocrine stimuli. Neuroplasticity is protective and initially promotes adaptations but when adaptive changes become prolonged, they produce a continuous burden that could lead to disease vulnerability called allostatic overload (McEwen, 2006). Morphologically, stress reduces the expression of dendritic spines and synaptic proteins and increases markers of apoptosis in the hippocampus. Electrophysiological evidence of diminished hippocampal function is obtained from studies showing reduced or absent long-term potentiation, a putative model of learning and synaptic plasticity. Clinically, reduced volume of the hippocampus from structural magnetic resonance imaging studies in depression and diabetes has provided evidence of similar deteriorating brain morphology as shown in animals exposed to stress (Eker and Gonul, 2010, McIntyre et al., 2010, Tata and Anderson, 2010).

An important function of the dentate gyrus of the hippocampus is in neurogenesis. The dentate gyrus is one of two established neurogenic zones in the brain, in addition to the subventricular zone, that continuously generates new neuronal cells throughout life (Leuner and Gould, 2010). Hippocampal neurogenesis is diminished by exposure to environmental stress, HPA axis hyperactivity and increased inflammation (Schoenfeld and Gould, 2012, Song and Wang, 2011, Zunszain et al., 2011). On the other hand, chronic exposure to antidepressant treatments increases hippocampal neurogenesis and may be responsible for the emergence of normal emotional behaviors in animals exposed to models of depression (Airan et al., 2007, Dranovsky and Hen, 2006, Jayatissa et al., 2008). Changes in neurogenesis alter a number of key functions of the hippocampus, such as learning and memory, affective expression and regulation of the HPA axis (Koehl and Abrous, 2011, Snyder et al., 2011). In the non-diabetic literature, extensive evidence supports the role of hippocampal neurogenesis in various types of learning and memory, including pattern separation (Bekinschtein et al., 2011, Clelland et al., 2009) and spatial memory (Goodman et al., 2010, Snyder et al., 2005). Further, “effortful learning” as well as learning spaced over a longer period of time improves memory as well as increases the survival of new hippocampal neurons (Shors et al., 2012, Sisti et al., 2007).

Hippocampal neurogenesis and neuroplasticity appears to be sensitive to many pathogenic and treatment factors that are associated with the comorbidity between diabetes and depression. A growing preclinical literature provides ample evidence that diabetes negatively affects the morphological integrity of the hippocampus and that reduced hippocampal neurogenesis, in concert with deficits of other forms of neuroplasticity, may contribute to comorbid cognitive and mood symptoms in diabetes. The goal of this review is to: (1) integrate existing information about the effects of diabetes on hippocampal neurogenesis and how altered neurogenesis may affect behavior, (2) review the effects of treatments in rodent models of diabetes that impact both hippocampal neurogenesis and behavioral outcomes, and (3) determine the necessary steps to move forward towards translation of the basic science research into humans.

Section snippets

Search methods

The keywords “diabet* neurogen*” were searched in PUBMED, MEDLINE, and EMBASE databases with the following limits: English language and published in the last 10 years (2001 to 2012). Article titles and abstracts were screened and potentially relevant articles were retrieved and evaluated. This review included published studies that examined the effect of diabetes on hippocampal neurogenesis (see Table 1), and it summarizes and synthesizes the highlights of selected articles. Other forms of

An overview of neurogenesis and measurement methods

Just a few years ago, neurogenesis was believed to occur only in the developing mammalian brain. However, with advances in cell labeling techniques, it was confirmed and accepted that neurogenesis is maintained and continues throughout adulthood in high abundance in specific brain regions, such as the hippocampus and the subventricular zone serving the olfactory bulbs (Elder et al., 2006, Taupin, 2006). Reports of neurogenesis in other areas of the brain exist, but the presence of constitutive

Effects of diabetes on hippocampal neurogenesis and behavior

Since T1D and T2D have similar but distinct metabolic consequences that could contribute to altered hippocampal neurogenesis and behavior in different ways, animal studies that model each type of diabetes will be discussed separately. First reviewed will be the literature examining the effects of experimental T1D and this will be followed by studies on the effects of experimental T2D. For each category or type of diabetes, the paper will discuss topics in the following order (1) effects of

Hippocampal neurogenesis

Over half of the rodent studies reviewed used a T1D model to study the effects of diabetes on the hippocampus (see Table 1). Investigators have studied experimental T1D using rodent models involving either administration of streptozotocin (STZ), a toxin that damages the pancreas, or the non-obese diabetic (NOD) mouse model, a genetic model that develops T1D.

Hippocampal neurogenesis

Hippocampal neurogenesis has been studied in a number of animal models of T2D (see Table 1). These models include genetic models in mice and rats, the db/db mouse, Zucker diabetic rat, and the Goto-Kakizaki rat. An environmental model of T2D that has been used commonly with rodents is prolonged exposure to a high fat diet or diet-induced obesity.

Experimental diabetes and other forms of hippocampal neuroplasticity

Neuroplasticity refers to the ability of the brain to adapt, change and reorganize throughout life. Hippocampal neurogenesis represents only one form of hippocampal neuroplasticity affected by diabetes. Other forms of hippocampal neuroplasticity include changes in hippocampal dendritic branching, long-term potentiation, and apoptosis. Their relevance to rodent models of diabetes will be discussed in the next section.

Measuring hippocampal neurogenesis in humans

Most research examining hippocampal neurogenesis would be expected to remain at the preclinical level primarily because techniques for measuring neurogenesis require post-mortem brain tissue. Further, patients with other illnesses, in addition to diabetes, may complicate findings relevant to neurogenesis. Nevertheless, human studies are necessary to move the science forward. Brain banks may provide access to a population of people who had diabetes and few other illnesses. Large scale

Future directions

The results from the majority of preclinical studies indicate that diabetes negatively impacts hippocampal cell proliferation and survival. Diabetes also produces evidence for dysfunction on other morphological and functional measures of hippocampal neuroplasticity, including dendritic remodeling, decreased long-term potentiation, and increased apoptosis, indicating diminished function of this brain region. In many studies, altered hippocampal neuroplasticity in diabetic rodents was accompanied

Summary and conclusions

Most preclinical models have shown that diabetes results in reduced hippocampal neurogenesis and neuroplasticity that may contribute to cognitive decline and depressive symptoms, two complications commonly observed in humans with diabetes. Currently, there is no diabetes-specific treatment for cognitive decline or depression in humans. There are some available treatments for depressed mood, but it is unclear how effective they are in people with comorbid diabetes and depression. Although the

Conflict of interest

None.

Acknowledgements

The authors thank Drs. Steven Arnold, Bethany Brookshire, Matthew R. Hayes, Sangwon Kim and Teresa Reyes for their helpful comments on a previous version of this manuscript. This work was supported by USPHS grants R01 MH86599 and F31 NR010853.

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