Long term consequences on spatial learning-memory of low-calorie diet during adolescence in female rats; hippocampal and prefrontal cortex BDNF level, expression of NeuN and cell proliferation in dent

Highlights

• Low-calorie in adolescence increases BDNF level in hippocampus and PFC in adulthood.

• Low calorie diet in adolescence may prevent age-related decline of cognition.

• Low-calorie in adolescence reduces oxidative stress in adulthood.

  
  

Abstract

Calorie restriction (CR) is argued to positively affect general health, longevity and normally occurring age-related reduction of cognition. Obesity during adolescence may adversely affect cognition in adulthood but, to date effects of CR have not been investigated. We hypothesized that feeding with as low as 15% low-calorie diet (LCD) during adolescence would increase hippocampal and prefrontal BDNF (Brain-derived neurotrophic factor) levels, proliferative cells and neuron numbers in dentate gyrus (DG), thus positively affecting spatial memory in adulthood. Spatial learning-memory function was improved in adult female Sprague–Dawley rats fed with LCD during adolescence. PCNA (Proliferating cell nuclear antigen-cell proliferation marker) expressing cells and NeuN (Neuronal nuclear antigen-neuron marker) expressing cells in hippocampus DG which are critically involved in memory were increased. Hippocampus and prefrontal cortex BDNF levels were increased while serum glucose levels and level of lipid peroxidation indicator malondialdehyde in serum and hippocampus were reduced. Our unique results suggest that improved cognition in adult rats with LCD feeding during adolescence may result from the increase of neurogenesis and BDNF. These findings reveal the importance of nutrition in adolescence for cognitive function in adulthood. Our results may be useful for further studies aiming to treat age-related cognitive impairments.

Introduction

Functional development of the hippocampus and frontal lobe—regions involved in spatial memory and cognitive control—continues throughout adolescence (Sherman et al., 2014). Hippocampus is an important brain area for learning and memory and where neurogenesis (formation of new neurons) occurs throughout life decreasing substantially with age (Abrous et al., 2005). New neurons consisting of proliferative cells in DG of hippocampus are capable of integrating into the existing neuronal circuitry and have been implicated to involve in hippocampus-dependent learning and memory tasks (Abrous et al., 2005). It is reported that not only hippocampus but also prefrontal cortex (PFC) is critical for spatial memory (Martinet et al., 2011). The existence of a direct pathway from the CA1 region of the hippocampus to the PFC represents a link between these two brain regions in mechanisms of learning and memory (Soares-Simi et al., 2013).

BDNF is widely expressed in hippocampus in the developing and adult brain and it is essential for the basal neurogenesis (Lee et al., 2002) and survival of neurons during development (Linnarsson et al., 2000). BDNF is also important for long-term potentiation (LTP) in hippocampus, which is considered to be the potential cellular mechanism underlying learning and memory (Figurov et al., 1996). Hippocampal BDNF level may be positively related to learning and memory efficiency (Gomez-Pinilla, 2008). BDNF expression in hippocampal–PFC circuits may play an important role in cognitive behavior in vivo. Disruption of activity-dependent BDNF expression impairs BDNF-dependent late phase LTP (lasting hours to days) in CA1, a site of hippocampal output to the PFC (Sakata et al., 2013). Recently it is reported that BDNF signaling may affect the maturation of synapses and function of the PFC, especially during adolescence (Guo et al., 2010). Unlike the hippocampus, where induction of LTP in the network is well-documented in relation to long-term memory, cognitive functions mediated by the PFC have been thought to be independent of long-lasting neuronal adaptation of the network. Nonetheless, interestingly, accumulating evidence suggests that the LTP; cellular machinery of synaptic plasticity plays an important role in cognitive functioning mediated by the PFC (Goto et al., 2010).

Several conditions, including stress and aging adversely affect hippocampal neurogenesis (Joëls et al., 2007). Corticosterone decreases proliferation and neurogenesis (Figurov et al., 1996) external stimuli including environmental enrichment and exercise stimulate neurogenesis in DG (Abrous et al., 2005). In recent years it has been shown that CR may also be an important factor positively affecting neurogenesis (Park and Lee, 2011), enhancing neuronal survival (Lee et al., 2002). CR refers to a reduced calorie intake by 20–40% without malnutrition with adequate micronutrient supplementation which promotes metabolic fitness, longevity and decreases the incidence and age of onset of many age-related diseases (diabetes, cardiovascular disease, and cancer) in rodent models of aging (Bordone and Guarente, 2005). CR also improves behavioral outcomes in some experimental models of neurodegenerative disorders and enhances spatial learning (Zainuddin and Thuret, 2012). Recent findings suggest that most of the beneficial effects of CR on the nervous system may result from the activation of adaptive responses; adaptive period immediately after the regimen is imposed and a steady state period, which can last the lifetime of the animal. During the adaptive phase CR promotes mitochondrial biogenesis, attenuates oxidative stress, lowers blood glucose and stays below-normal level during the steady state period (Maalouf et al., 2009). CR increases the expression of BDNF, most prominently in the hippocampus and BDNF mediates adaptive responses (Maalouf et al., 2009). It is reported that BDNF contributes to the positive effect of CR on neurogenesis by promoting the survival of newly generated neurons (Lee et al., 2002).

Because during adolescence energy need is higher and the brain undergoes a major remodeling, it is very sensitive to external factors such as diet and stress (Sherman et al., 2014). Although it is known that obesity in adolescence adversely affect cognition in adulthood (Boitard et al., 2014), to date the effects of CR have not been studied. Furthermore, it is known that especially adolescent girls apply diet because of physical appearance sensitivity (Huon et al., 2000).

We hypothesized that feeding with as low as 15% LCD during adolescence in female rats would increase hippocampal and prefrontal BDNF levels, proliferative cells and neuron numbers in DG, thus positively affect spatial memory in adulthood. We further postulated that if CR creates adaptation at cellular level, the possible positive effect of LCD applied in adolescence on cognitive function in adulthood may be linked to lower oxidative stress products in serum and hippocampus and decreased serum glucose level.

Daily food intake and weight gain

The daily food intake of each group was monitored during the experiment. In terms of daily food intake, there was no significant difference between the Control-SD groups and LCD. However, LCD groups gained less weight than Control-SD groups (p<0.05) (Fig. 1).

Learning phase

At the end of the learning phase the escape latency of all rats was under 10 s, they have learned the location of the probe. In all groups the escape latency in third day decreased significantly compared to the first day (p<0.001) (Fig. 2).

Probe test

Discussion

Our results showed that learning and memory were improved in adult female rats fed with 15% LCD in adolescence. Also, LCD in adolescence increased cell proliferation and number of neurons in DG and BDNF level of hippocampus and PFC, decreased serum glucose and MDA levels. To our knowledge, this is the first study to address the influence of 15% LCD during adolescence on spatial learning, memory in adulthood.

Adolescence is the period when the brain development continues and the brain is most

Conclusion

Our findings revealed that feeding with LCD in adolescence increases cell proliferation, neuron number in DG and BDNF levels in hippocampus and PFC, and improves the performance of rats in water maze. This may suggest that increased neurogenesis correlates with improved cognition. In addition, nutrition with LCD as low as 15% in adolescence may induce irreversible adaptive responses such as reduced MDA levels in serum, hippocampus and attenuated glucose levels in serum in adulthood. Our

Animals

Thirty-six female Sprague–Dawley rats were obtained from Istanbul University, DETAE (Turkey) on postnatal day (PND) 21. The rats were maintained under standard conditions (ambient temperature 22 °C, 12 h light/dark cycle, light on at 7:00 a.m.) with ad libitum access to food and water during one week. The experiments were performed in accordance with the ethical guidelines of Istanbul University, HADYEK, 2013/118.

Experimental design

On PND 28, rats were separated into four groups as 2 LCD and 2 standard diet

Conflict of interest

The authors report that they have no conflicts of interest.

Acknowledgment

The fine revision of the text done by Prof. Dr AS Diler is appreciated. The present work was supported by the Research Fund of Istanbul University (Istanbul University Scientific Research Projects - Project no.: 38750), Istanbul, Turkey.

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