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Declining global DNA methylation and cognitive impairment are reported to occur in the normal aging process. It is not known if DNA methylation plays a role in the efficacy of memory-enhancing therapies. In this study, aged animals were administered prelimbic cortical deep brain stimulation (PrL DBS) and/or Lmethionine (MET) treatment. We found that PrL DBS and MET (MET-PrL DBS) co-administration resulted in hippocampal-dependent spatial memory enhancements in aged animals. Molecular data suggested MET-PrL DBS induced DNA methyltransferase DNMT3a-dependent methylation, robust synergistic upregulation of neuroplasticity-related genes, and simultaneous inhibition of the memory-suppressing gene calcineurin in the hippocampus. We further found that MET-PrL DBS also activated the PKA-CaMKIIa-BDNF pathway, increased hippocampal neurogenesis, and enhanced dopaminergic and serotonergic neurotransmission. We next inhibited the activity of DNA methyltransferase (DNMT) by RG108 infusion in the hippocampus of young animals to establish a causal relationship between DNMT activity and the effects of PrL DBS. Hippocampal DNMT inhibition in young animals was sufficient to recapitulate the behavioral deficits observed in aged animals and abolished the memory-enhancing and molecular effects of PrL DBS. Our findings implicate hippocampal DNMT as a therapeutic target for PrL DBS and pave way for the potential use of non-invasive neuromodulation modalities against dementia. [ABSTRACT FROM AUTHOR]

The serotonergic precursor tryptophan and the dopaminergic precursor tyrosine have been shown to be important modulators of mood, behaviour and cognition. Specifically, research on the function of tryptophan has characterised this molecule as particularly relevant in the context of pathological disorders such as depression. Moreover, a large body of evidence has now been accumulated to suggest that tryptophan may also be involved in executive function and reward processing. Despite some clear differentiation with tryptophan, the data reviewed in this paper illustrates that tyrosine shares similar functions with tryptophan in the regulation of executive function and reward, and that these processes in turn, rather than acting in isolation, causally influence each other. [ABSTRACT FROM AUTHOR]

Serotonin has been shown to modulate probabilistic reversal learning (PRL) and negative feedback sensitivity (NFS) in both animal and human studies. Whilst these two measures are tightly coupled, some studies have suggested that these may be mediated by independent mechanisms; the former, representing perseveration and cognitive flexibility, and the latter measuring the ability to maintain a response set (win-stay) at the expense of lose-shift behavior when occasional misleading feedback has been presented. Here, we tested this hypothesis in 44 healthy participants who were administered tryptophan (22 placebo, 22 tryptophan), a precursor to serotonin. We found a dissociable effect of tryptophan supplementation on PRL/NFS. Specifically, tryptophan administration increased NFS compared to the placebo group but had no effect on PRL. We discuss these findings in relation to dosages and with a particular focus on the acute tryptophan depletion (ATD) procedures. [ABSTRACT FROM AUTHOR]

Background: The catecholaminergic precursor to dopamine, tyrosine, is an important modulator of cognitive performance. A number of studies have demonstrated that the beneficial effects of tyrosine on cognitive performance are most pronounced when individuals are exposed to stressful situations, such as hypothermia. However, little is known about whether manipulation of stress using non-aversive stimuli, such as cognitive demand, can also bring about similar improvements.Methods: We conducted a randomized, double-blind, placebo-controlled experiment to test the effects of tyrosine administration and cognitive load (low or high) on cognitive flexibility, a measure known to be influenced by catecholaminergic function. A total of 70 healthy volunteers completed a baseline cognitive flexibility test (Wisconsin Card Sorting Test: WCST). Participants were given a dose of either tyrosine (2.0 g) or placebo (cellulose) and subject to either low cognitive load (simple reaction time task) or high cognitive load (digit memory span task), immediately followed by a WCST for a second time.Results: Contrary to expectations, we found that instead of ameliorating performance under the high cognitive load condition, tyrosine worsened cognitive flexibility.Limitations: Physiological marker of stress was not measured.Conclusions: Our results suggest that aversive stressors and cognitive demand modulate the effects of tyrosine on cognitive performance in a differential manner. [ABSTRACT FROM AUTHOR]