Memory loss in older people is a serious and widespread problem that affects up to 50% of those over the age of 85. It is a key symptom of dementia, but despite the growing impact of this disease on society, there are no treatments currently available that can effectively stop or delay the progression of the symptoms.

One therapy that may reduce memory loss is called deep brain stimulation. Electrodes are implanted into the brain and used to stimulate brain cells in particular areas of the brain to alter mental and emotional processes. Deep brain stimulation is already used to treat Parkinson's disease, depression and other conditions that affect how the brain works.

Liu et al. studied the effect of deep brain stimulation on memory in rats. The experiments show that middle-aged rats performed less well in short- and long-term memory tests than young rats. Next, Liu et al. investigated whether deep brain stimulation could improve memory in the middle-aged rats. The electrodes were positioned to stimulate a region near the front of the brain called the ‘ventromedial prefrontal cortex’; this region is important for the formation and recall of memories. Liu et al. then gave the rats a series of memory tasks that tested their recall after 90 minutes (to test their short-term memory), and after 24 hours (to test long-term memory).

The experiments reveal that a brief stimulation of brain cells in this region of the brain improved the rats' short-term memory, but not their long-term memory. However, more sustained stimulation of this region of the brain improved both the short-term and long-term memory of the rats. Furthermore, deep brain stimulation led to the formation of new brain cells in another region of the brain called the hippocampus, which is also involved in memory. The hippocampus had not been in direct contact with the electrodes so the increase in brain cells was due to its connections with the stimulated ventromedial prefrontal cortex.

Liu et al.'s findings suggest that deep brain stimulation of the ventromedial prefrontal cortex has the potential to be developed into a therapy to treat dementia and other conditions that lead to memory loss in humans.

Memory loss is the key symptom of dementia-related disorders along with impaired cognitive functioning such as language or reasoning. It is usually caused by Alzheimer's disease and other age-related dementia. Its prevalence doubles from a low rate in 60–64 age group to 40–50% of those older than 85 (Lobo et al., 2000). Dementia is a progressive disease, which has a detrimental impact on the quality of life for patients. To date, pharmacological treatments for dementia have limited effects and there are no known treatments that cure or delay the progression of this memory impairment (Doody et al., 2014; Salloway et al., 2014). Therefore, a novel non-pharmacological approach such as deep brain stimulation (DBS) is currently considered as an alternative treatment to reduce the symptomatic and progression of this memory deterioration (Hescham et al., 2013a).

DBS, a technique of minimally invasive surgical implantation of electrodes with delivering of electrical impulses into the brain, has been demonstrated to control a wide range of neurological disorders and neuropsychiatric diseases (Sesia et al., 2009; Temel et al., 2012b; Temel and Lim, 2013). In line with these developments, evidence from recent studies suggests that DBS might enhance memory functions when particular brain areas are stimulated (Hamani et al., 2008; Laxton et al., 2010; Suthana et al., 2012; Hescham et al., 2013b). Of particular interest, DBS of the subgenual anterior cingulate cortex or the ventromedial prefrontal cortex (vmPFC) induced striking antidepressant activity in both patients and animal studies (Mayberg et al., 2005; Lozano et al., 2008; Hamani et al., 2010b; Kennedy et al., 2011; Temel and Lim, 2013; Lim et al., 2015b). Despite encouraging results, no studies have shown the putative role of vmPFC DBS in learning and memory performance. In the realm of cognitive function, there is empirical evidence indicating that vmPFC plays an important role in the formation, consolidation, and retrieval of memory, as well as reward and decision making (Maviel et al., 2004; Euston et al., 2012). Based on the human imaging and rodent studies, the vmPFC was significantly activated during the recall of remote memory (Bontempi et al., 1999; Takashima et al., 2006a, 2006b; Gais et al., 2007), while its inactivation caused memory impairment when tested in the radial arm-maze (Maviel et al., 2004), the Morris water-maze (MWM) (Teixeira et al., 2006), and the contextual fear conditioning (Frankland et al., 2004). In line with these studies, malfunctioning has also been reported in the hippocampus and the vmPFC (which received robust projections from the hippocampal formation) in early stages of Alzheimer's disease, frontotemporal dementia, and healthy aging-related memory impairments (Salat et al., 2001; Lindberg et al., 2012).

Given the potential mechanisms involved by DBS including the increase of hippocampal brain-derived neurotrophic factor (BDNF) levels (Hamani et al., 2012; Ying et al., 2012) and neurogenesis-related functions (Toda et al., 2008; Kadar et al., 2011; Stone et al., 2011), we tested the hypothesis that vmPFC DBS-enhanced memory function by modulating the hippocampal neurogenic activity in the middle-aged rat model with aging-related memory impairment. The use of this animal model was supported by previous data that showed aged-related deficits in both the memory and the hippocampal functioning (Rex et al., 2005; Kaczorowski and Disterhoft, 2009). In acute DBS, animals were tested with either high- or low-frequency stimulation (HFS or LFS) at various amplitudes using the conventional novel-object recognition (NOR) test. Subsequently, another set of animals was used to assess the chronic stimulation effects on memory enhancement using the NOR and the MWM tests. For investigation of the underlying mechanism, we analyzed the effects of chronic stimulation on the molecular and cellular levels of hippocampal neurogenesis-related functions.

The present findings confirm the results of previous studies of progressive age-related memory impairment in the middle-aged rats (Rex et al., 2005; Kaczorowski and Disterhoft, 2009). We next conducted electrical stimulation in this animal model of memory deficit, using HFS and LFS with various stimulation current intensities in the NOR test. Our results showed that HFS at 200 μA and LFS at 50, 200, and 400 μA significantly enhanced the memory functions in the short-, but not the long-term memory retention interval when compared to the sham. We next carried out chronic stimulation in this middle-aged rat model. We hypothesized that chronic stimulation would increase both the short- and long-term memory functions via a mechanism of enhanced hippocampal neuroplasticity. Previous studies have shown that memory deficits were partly due to the disruption of the hippocampal neuroplasticity (Deupree et al., 1993; Rex et al., 2005). Therefore, our hypothesis was driven by findings that DBS in various brain targets increased BDNF level (Hamani et al., 2012; Ying et al., 2012) and enhanced neurogenesis-related functions (Toda et al., 2008; Kadar et al., 2011; Stone et al., 2011) in the hippocampus. Further, this hypothesis was also supported by the fact that the increased BDNF level and neurogenesis function in the hippocampus were strongly correlated with the hippocampal-dependent memory tests (Drapeau et al., 2003; Erickson et al., 2011). Thus, after chronic stimulation, we found significant improvement in both the short- and long-term memories in the NOR test, as well as the spatial memory performances during the MWM task as compared to the sham.

In the acute stimulation experiment, we found that the behavioral effects of vmPFC stimulation were dependent on the stimulation frequency and current intensity. Although these findings are consistent with previous reports (Hamani et al., 2010a; Hescham et al., 2013b), the mechanisms of the stimulation parameter dependency in regulation of memory functions remain largely obscure. Nonetheless, it is postulated that the neurons in the vmPFC are highly sensitive to specific stimulation settings for induction of either long-term potentiation (LTP) or depression (LTD). This notion was highly supported by the findings in which the vmPFC synapses are potentially vulnerable to LTP or LTD strengthening after specific type of stimulation (Herry and Garcia, 2002). It has been found that the prefrontal cortex neurons could undergo LTP with rapid and stable potentiation in the prelimbic synapses after high-frequency tetanic stimulation of the hippocampal CA1/subicular region (Laroche et al., 1990). Such a LTP-like plasticity in the vmPFC after hippocampal HFS has been shown to be dependent on α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA)-receptor, which indicates a crucial role for the synaptic potentiation in the hippocampal-vmPFC pathway in rapid memory consolidation (Laroche et al., 2000). Although HFS and LFS at specific amplitudes were effective for memory enhancement, it is noteworthy that LFS induced negative effects on the anxiety-related behaviors (Lim et al., 2015b). Furthermore, HFS of the vmPFC has been shown to reduce conditioned fear and enhance the extinction of aversive memory (Milad and Quirk, 2002; Milad et al., 2004), in contrast to LFS, which induced impairment in extinction of conditioned fear (Shehadi and Maroun, 2012). Since previous studies of vmPFC HFS produced robust antidepressant-like behaviors (Lim et al., 2015a, 2015b), we therefore applied this stimulation parameter in the chronic stimulation experiment to test the hypothesis that it would restore the memory deficits for both the short- and long-term memory functions of the middle-aged rats.

As might be expected for the effects after chronic stimulation, there was an improvement on memory function in the short- but not the long-term memory retention interval when the animals were tested with no-HFS prior to the NOR task. Strikingly, we found a remarkable reversal of memory deficits in both the short- and long-term memory of the animals that received HFS prior to the NOR test as compared to the non-stimulated sham. Congruently, chronic vmPFC HFS significantly improved the spatial navigation performances when conducted in a hippocampal-dependent memory MWM test. In the present data, we clearly distinguished a role for the vmPFC in regulation of both the short- and long-term memory functions. In most studies, short-term memory is generally regarded as memory spanning from seconds to several minutes or hours, while long-term memory is usually last from hours to several days or longer (Nagai et al., 2007; Euston et al., 2012). Albeit many studies have indicated that vmPFC is involved in the expression of long-term memory (Maviel et al., 2004; Teixeira et al., 2006), there are also findings supporting that vmPFC is involved in consolidation and retrieval of recently acquired memories (Blum et al., 2006; Leon et al., 2010). Thus, it is likely that the vmPFC HFS potentiated the initial hippocampal encoding during the acquisition phase, which was then followed by enhanced retrieval during the short- and long-term memory recalls. Taken together, these findings further implicate a specific role for the vmPFC HFS in facilitation of rapid consolidation and retrieval of the short- and long-term memory processes in the hippocampus.

HFS of the vmPFC has not only been demonstrated for memory enhancement in the middle-aged memory deficit rat model, but also induced profound antidepressant-like behaviors in the experimental animal studies (Lim et al., 2015a; 2015b). Interestingly, the effects of memory improvement by vmPFC HFS, as characterized by the increased novelty seeking in the NOR and MWM tasks, were highly associated with the stimulation effects on reduction in anxiety behavior. These results confirm previous findings that animals with lower anxiety or fear level displayed higher novelty seeking behavior, particularly in the elevated plus-maze and light–dark box tests (Kabbaj et al., 2000; Stead et al., 2006). In consistent with the data found in the animal model of depression, rats undergoing chronic stress exhibited anxious and low exploratory behaviors (Lim et al., 2015b), as well as impairment in spatial memory task performances (Conrad et al., 1996; Beck and Luine, 1999). Apparently, chronic stress produces pathological alterations on the molecular and morphological levels in the hippocampus that is involved in the regulation of both the spatial memory formation and emotional behaviors. Thus, our experiments found that the memory enhancement effect is likely to be accompanied by the vmPFC DBS-induced anxiolytic effects via the mechanisms of neurogenesis and dendritic remodeling in the hippocampal neurons.

Given the prominent anatomical connectivity between the hippocampus and vmPFC (Jay and Witter, 1991; Cenquizca and Swanson, 2007), it was observed that vmPFC HFS drove the local neural activity as characterized by c-Fos-ir activation in the subiculum, DG, as well as a marginal increase in the CA1 field of the hippocampus. Although there is no direct connection from vmPFC to the hippocampus, it is possible that the effects of vmPFC HFS on the hippocampal neural activity are mediated by a reciprocal bisynaptic pathway through the nucleus reunions or the lateral entorhinal cortex (Burwell and Amaral, 1998; Vertes et al., 2007). Besides, the neural activity in the hippocampus could probably be activated by either antidromic or orthodromic stimulation that possibly achieved by a current spread from the vmPFC structure to the neighboring axon bundles—the minor forceps of the corpus callosum (Lim et al., 2015b). As a result, the hippocampal regions would eventually be activated for an induction of LTP to strengthen its synaptic plasticity for memory processes. Of particular interest, a tractography analysis by diffusion tensor imaging provides evidence for this structural connectivity that HFS of the subgenual cingulate gyrus (generally considered to be homologue of the rat vmPFC), showed connections to the medial frontal cortex, anterior and posterior cingulate, and the anterior medial temporal lobe (i.e., amygdala-hippocampus) (Gutman et al., 2009). The connections of the hippocampus and amygdala to the vmPFC have been previously investigated by anatomical and electrophysiological studies (Laroche et al., 1990; Jay and Witter, 1991). It has been shown that the excitatory and inhibitory inputs from the amygdala and hippocampus were converged and interact in the vmPFC (Ishikawa and Nakamura, 2003), implying that activation of the amygdalar-hippocampal neurons might be crucial for vmPFC neurons in memory regulation. More importantly, the electrophysiological studies have provided concrete evidence of functional interaction between the vmPFC and hippocampus in which their theta oscillations were highly synchronized as measured by both the spike-theta phase locking and local field potential coherence, during memory acquisition and retrieval in spatial tasks (Jones and Wilson, 2005; Siapas et al., 2005; Benchenane et al., 2010). Based on this evidence, we suggested that the rapid encoding and retrieval of memory depend largely on the bidirectional regulation of synaptic connectivity between the vmPFC and hippocampus; while the disruption of its connection affect the learning and memory functions, which are commonly identified in patients suffering from dementia (Salat et al., 2001).

In line with our findings, HFS of the anterior nucleus of the thalamus and the entorhinal cortex has been demonstrated to increase neurogenesis (Toda et al., 2008) and memory functions, particularly spatial memory measured in the MWM (Stone et al., 2011) and enhanced performance on a delayed non-matching to sample task (Hamani et al., 2011). In this study, we found that vmPFC HFS induced upregulation of neurogenesis-associated genes with increased neural progenitors cells and dendritic spines in the DG of the hippocampus. In agreement with our previous microarray data (Kadar et al., 2011), chronic HFS has been shown to modulate the hippocampal genes that involved in the proliferation and neurogenesis-related functions, as well as genes supporting for neural differentiation, migration and maturation. Although we observed no differences for the Timp1 (neuroprotection), Ccl2 (neural differentiation), and BDNF (synaptic plasticity) gene expression, there was an overall increase in their fold-change with approximately 1.2–2 fold after chronic vmPFC HFS. Notably, we found a strong induction of upregulation in the Angpt2 gene (4.8-fold) that promotes neuronal differentiation, migration and neuroprotection (Liu et al., 2009), as well as NeuN/Rbfox3 gene (2-fold), which plays an essential role for neural progenitor cells differentiation and maturation (Kim et al., 2009, 2013). Further, our present observations were also supported by earlier works demonstrating that vmPFC HFS induced significant increase of BDNF and serotonin (5-HT) levels in the hippocampus (Hamani et al., 2012). Recent studies have shown that the increase of 5-HT and BDNF expression in the hippocampus regulate synaptic plasticity, as well as cognitive and mood-related behaviors. It is well-known that both the 5-HT and BDNF promote neurogenesis by enhancing the synaptogenesis, neuronal differentiation, and survival particularly for memory acquisition and consolidation (Gaspar et al., 2003; Lu and Chang, 2004; Pang et al., 2004). Although no microdialysis data were provided with regard to the extracellular levels of 5-HT and BDNF after chronic vmPFC HFS, the increased neurogenesis effects as obtained from this study clearly indicate that its plausible mechanism is facilitated by the release of 5-HT and enhanced BDNF levels (Hamani et al., 2012). Importantly, the vmPFC HFS effects on the behavioral observation of improved memory functions and the neurogenesis have indicated that a strong synaptic network circuitry has been established within the DG for integration of new information and memory storage. In support of this notion, previous studies have demonstrated that the increased neurogenesis was highly associated with enhanced learning and memory, while its decrease caused memory impairment (van Praag et al., 1999; Shors et al., 2001). Although the present study has identified the DBS-induced memory enhancement by neurogenesis, there is a possibility that these effects are mediated by other non-neurogenic mechanisms such as modulation of the neurotransmission (via acetylcholine, dopamine, 5-HT, etc), synaptic potentiation by the AMPA/NMDA receptor trafficking, and enhancement of the BDNF or CREB (cAMP response element-binding protein) function (Hamani et al., 2012; Stern and Alberni, 2012).

The above findings prompted us to further examine whether the increase of neurogenesis-related functions is associated with the effects of memory enhancement by vmPFC HFS. Our correlation analysis of gene expression revealed that the Syn was strongly associated with the Nes and Dcx genes, suggesting that vmPFC HFS might possibly cause an alteration of increased dendritic synaptogenesis, particularly in the hippocampal DG where transcriptional process for Nes and Dcx genes occurs. Consistent with this interpretation, we have demonstrated the increase of dendritic spines in the Golgi-impregnated cells of the hippocampal DG. This observation was supported by a previous study which showed that electrical stimulation affected the axonal path in cultured Xenopus neurons that was mediated by elevation of both cytoplasmic Ca²⁺ and cyclic adenosine monophosphate levels (Ming et al., 2001). Importantly, our behavioral correlates show that the spatial memory performances were associated with the cell proliferation in the DG, indicating that neurogenesis in the DG is vital for the hippocampal-dependent learning and memory processes.

In conclusion, our findings suggest that chronic vmPFC HFS induces long-lasting effects on memory performances and its underlying mechanism is possibly mediated by an enhanced neurogenesis in the hippocampus. Despite the fact that this structure has been previously shown for antidepressant-like activities, it might as well serve as a new effective DBS target for aged-related memory deficits. Thus, this translational research provides an additional window for a possibility of future clinical trials on this potential brain target for memory enhancement.

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Author details

1. Albert Liu

   School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

   Contribution

   AL, Analyzed parts of the behavioural and histochemical data

   Competing interests

   The authors declare that no competing interests exist.

2. Neeraj Jain

   School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

   Contribution

   NJ, Conducted parts of the real-time PCR experiments

   Competing interests

   The authors declare that no competing interests exist.

3. Ajai Vyas

   School of Biological Sciences, Nanyang Technological University, Singapore, Singapore

   Contribution

   AV, Contributed to part of the data analysis and comments on the manuscript

   Competing interests

   The authors declare that no competing interests exist.

4. Lee Wei Lim

   1. School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
   2. Department of Biological Sciences, Sunway University, Bandar Sunway, Malaysia

   Contribution

   LWL, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   For correspondence

   drlimleewei@gmail.com

   Competing interests

   The authors declare that no competing interests exist.

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