Overcoming aversive emotional memories requires neural systems that detect when fear responses are no longer appropriate so that they can be extinguished. The midbrain ventral tegmental area (VTA) dopamine system has been implicated in reward and more broadly in signaling when a better-than-expected outcome has occurred. This suggests that it may be important in guiding fear to safety transitions. We report that when an expected aversive outcome does not occur, activity in midbrain dopamine neurons is necessary to extinguish behavioral fear responses and engage molecular signaling events in extinction learning circuits. Furthermore, a specific dopamine projection to the nucleus accumbens medial shell is partially responsible for this effect. In contrast, a separate dopamine projection to the medial prefrontal cortex opposes extinction learning. This demonstrates a novel function for the canonical VTA-dopamine reward system and reveals opposing behavioral roles for different dopamine neuron projections in fear extinction learning.

Background: Recent evidence suggests that transcranial direct current stimulation (tDCS) may interact with the dopaminergic system to affect cognitive flexibility. Objective/hypotheses: We examined whether putative reduction of dopamine levels through the acute phenylalanine/tyrosine depletion (APTD) procedure and excitatory anodal tDCS of the dorsolateral prefrontal cortex (dlPFC) are causally related to cognitive flexibility as measured by task switching and reversal learning. Method: A double-blind, sham-controlled, randomised trial was conducted to test the effects of combining anodal tDCS and depletion of catecholaminergic precursor tyrosine on cognitive flexibility. Results: Anodal tDCS and tyrosine depletion had a significant effect on task switching, but not reversal learning. Whilst perseverative errors were significantly improved by anodal tDCS, the APTD impaired reaction times. Importantly, the combination of APTD and anodal tDCS resulted in cognitive performance which did not statistically differ to that of the control condition. Conclusions: Our results suggest that the effects of tDCS on cognitive flexibility are modulated by dopaminergic tone.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the hallmark pathologies of amyloid-beta plaques and neurofibrillary tangles. Symptoms of this devastating disease include behavioral changes and deterioration of higher cognitive functions. Impairment of neurogenesis has also been shown to occur in AD, which adversely impacts new neuronal cell growth, differentiation, and survival. This impairment possibly results from the cumulative effects of the various pathologies of AD. Preclinical studies have suggested that the administration of melatonin-the pineal hormone primarily responsible for the regulation of the circadian rhythm-targets the effects of AD pathologies and improves cognitive impairment. It is postulated that by mitigating the effect of these pathologies, melatonin can also rescue neurogenesis impairment. This review aims to explore the effect of AD pathologies on neurogenesis, as well as the mechanisms by which melatonin is able to ameliorate AD pathologies to potentially promote neurogenesis.

Catecholaminergic modulation of indices of cognitive flexibility:a pharmaco-tDCS study. Brain Stimulation. (In Press