The Evidence for Altered BDNF Expression in the Brain of Rats Reared or Housed in Social Isolation: A Systematic Review

MINI REVIEW published: 31 May 2017 doi: 10.3389/fnbeh.2017.00101 The Evidence for Altered BDNF Expression in the Brain of Rats Reared or Housed in Social Isolation: A Systematic Review Jana Murínová 1 , Nataša Hlaváčová 2 , Magdaléna Chmelová 2 and Igor Riečanský 1, 3* 1 Laboratory of Cognitive Neuroscience, Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, Bratislava, Slovakia, 2 Laboratory of Pharmacological Neuroendocrinology, Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia, 3 Social, Cognitive and Affective Neuroscience Unit, Department of Basic Psychological Research and Research Methods, Faculty of Psychology, University of Vienna, Vienna, Austria Edited by: Francesca Cirulli, Istituto Superiore di Sanità, Italy Reviewed by: Stephen D. Ginsberg, Nathan Kline Institute for Psychiatric Research, United States Joerg Bock, Otto-von-Guericke University Magdeburg, Germany Darlene A. Kertes, University of Florida, United States *Correspondence: Igor Riečanský Received: 27 February 2017 Accepted: 12 May 2017 Published: 31 May 2017 Citation: Murínová J, Hlaváčová N, Chmelová M and Riečanský I (2017) The Evidence for Altered BDNF Expression in the Brain of Rats Reared or Housed in Social Isolation: A Systematic Review. Front. Behav. Neurosci. 11:101. doi: 10.3389/fnbeh.2017.00101 There is evidence that development and maintenance of neural connections are disrupted in major mental disorders, which indicates that neurotrophic factors could play a critical role in their pathogenesis. Stress is a well-established risk factor for psychopathology and recent research suggests that disrupted signaling via brain-derived neurotrophic factor (BDNF) may be involved in mediating the negative effects of stress on the brain. Social isolation of rats elicits chronic stress and is widely used as an animal model of mental disorders such as schizophrenia and depression. We carried out a systematic search of published studies to review current evidence for an altered expression of BDNF in the brain of rats reared or housed in social isolation. Across all age groups (post-weaning, adolescent, adult), majority of the identified studies (16/21) reported a decreased expression of BDNF in the hippocampus. There are far less published data on BDNF expression in other brain regions. Data are also scarce to assess the behavioral changes as a function of BDNF expression, but the downregulation of BDNF seems to be associated with increased anxiety-like symptoms. The reviewed data generally support the putative involvement of BDNF in the pathogenesis of stress-related mental illness. However, the mechanisms linking chronic social isolation, BDNF expression and the elicited behavioral alterations are currently unknown. Keywords: neurotrophic factors, neural plasticity, mental disorders, schizophrenia, depression, animal models, chronic stress, isolation rearing INTRODUCTION Evidence has been accumulated that development, maturation, and maintenance of neural connections play a critical role in the pathogenesis of major mental illness including depression, schizophrenia, and bipolar disorder. These developmental and homeostatic neural processes are controlled by neurotrophic factors, signaling peptides which act on specific receptors to regulate the physiology of neurons and glial cells (Williams and Umemori, 2014). There are several families of growth factors acting in the brain, including many various molecules. Of these, brain-derived neurotrophic factor (BDNF) has attracted a great deal of attention as probably being importantly involved in various neuropsychiatric diseases (Autry and Monteggia, 2012; Castrén, 2014). Frontiers in Behavioral Neuroscience | www.frontiersin.org 1 May 2017 | Volume 11 | Article 101 Murínová et al. Social Isolation Alters BDNF live in groups and preventing them of social contacts and interaction for a longer time deprives them of important stimuli and represents a significant stressor (Hatch et al., 1965; Hawkley et al., 2012). Chronic social isolation induces a variety of symptoms in rats, including depression-, anxiety-, and psychosislike behaviors, but also signs of autonomic, neuroendocrine, and metabolic dysregulation (Fone and Porkess, 2008; Karelina and DeVries, 2011; Cacioppo et al., 2015). The terms isolation rearing or isolation housing are commonly used to denote social isolation of adolescent (post-weaning) or adult rats, respectively. The consequences of isolation are more severe in rats compared with other rodent species (Einon et al., 1981) and it has been argued that social isolation of rats has a good etiological validity to model human mental illness (Powell, 2010; Czéh et al., 2016). Given the emerging important role of BDNF in stress-related mental disorders, the aim of our investigation was to systematically summarize current evidence for altered BDNF signaling in experimental studies employing chronic social isolation of rats. BDNF is a member of the neurotrophin family of growth factors, which also includes nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4; Bothwell, 2014). Similarly to other neurotrophins, BDNF is first synthesized as a precursor protein, proBDNF, which is cleaved to the mature form (Deinhardt and Chao, 2014). BDNF binds primarily to a transmembrane receptor TrkB (tropomyosin receptor kinase B or tyrosine receptor kinase B). NT-4 binds preferentially to TrkB as well, while NGF has highest affinity for TrkA and NT-3 for TrkC receptor. Proneurotrophins, including proBDNF, are also biologically active and all bind to a pan-selective p75 neurotrophin receptor (Lu et al., 2005). Mature neurotrophins are also able to interact with p75 receptor but with low affinity. Through activation of Trk and p75 receptors, respectively, mature neurotrophins and proneurotrophins may produce opposing effects on target cells. Thus, while proBDNF mediates apoptosis and long-term synaptic depression, mature BDNF rather supports neuronal survival, growth, differentiation, and synaptic long-term potentiation (Roux and Barker, 2002; Yoshii and Constantine-Paton, 2010). Throughout the development, BDNF plays a crucial role in cellular proliferation, migration, and phenotypic differentiation (Huang and Reichardt, 2001; Poo, 2001). BDNF is also required in the mature brain for maintenance of neuronal functions, structural integrity of neurons and neurogenesis (Poo, 2001; Autry and Monteggia, 2012). In patients with schizophrenia, depression and bipolar disorder, reduced expression of BDNF and/or TrkB has been found in the hippocampus and multiple cortical areas (Autry and Monteggia, 2012; Castrén, 2014) and there is also evidence for reduced BDNF levels in the peripheral blood in these disorders (Fernandes et al., 2014). Recent research indicates that BDNF may create an important link between stress and mental illness. St (...truncated)