Impact of partial dopamine depletion on cognitive flexibility in BDNF heterozygous mice

Abstract

Rationale Cognitive flexibility is a key component of executive function and is disrupted in major psychiatric disorders. Brain-derived neurotrophic factor (BDNF) exerts neuromodulatory effects on synaptic transmission and cognitive/affective behaviors. However the causal mechanisms linking BDNF hypofunction with executive deficits are not well understood. Objectives Here, we assessed the consequences of BDNF hemizygosity on cognitive flexibility in mice performing an operant conditioning task. As dopaminergic-glutamatergic interaction in the striatum is important for cognitive processing, and BDNF heterozygous (BDNF+/−) mice display a higher dopamine tone in the dorsal striatum, we also assessed the effects of partial striatal dopamine depletion on task performance and glutamate release. Results BDNF+/− mice acquired discrimination learning as well as new rule learning during set-shifting as efficiently as wild-type mice. However, partial removal of striatal dopaminergic inputs with 6-hydroxydopamine (6-OHDA) impaired these cognitive processes by impeding the maintenance of a new learning strategy in both genotypes. BDNF mutants exhibited performance impairments during reversal learning and these deficits were associated with increased perseveration to the previously acquired strategy. Partial dopamine depletion of the striatum reversed these cognitive impairments. Additionally, reduction in depolarization-evoked glutamate release noted in the dorsal striatum of BDNF+/− mice was not observed in 6-OHDA-infused BDNF mutants indicating normalization of glutamatergic transmission in these animals. Conclusions Our data illustrate that BDNF signaling regulates cognitive control processes presumably by maintaining striatal dopamine-glutamate balance. Moreover, aberrations in BDNF signaling may act as a common neurobiological substrate that accounts for executive dysfunction observed in multiple psychiatric conditions.

Serum Brain-Derived Neurotrophic Factor, and Plasma Catecholamine Metabolites in People with Major Depression: Preliminary Cross-Sectional Study

“…The main finding of the present study was that plasma levels of catecholamine metabolites were not associated with serum BDNF levels, even though catecholamine might influence BDNF synthesis and secretion in the brain ( 21 ) and BDNF might play an important role in the synthesis and/or secretion of catecholamine ( 22 ). We have previously reported a negative correlation between plasma MHPG and serum BDNF in healthy workers ( 13 , 14 ).…”

It takes two to tango: Dorsal direct and indirect pathways orchestration of motor learning and behavioral flexibility

“…Conversely, reducing DA levels by pharmacological depletion of DA neurotransmission in the DMS impairs odor-guided reversal learning, without affecting initial discrimination learning (O'Neill and Brown, 2007). A similar depletion targeting more largely the DS induces a deficit in the acquisition of a visual discrimination task, and alters the acquisition of a new rule in a set-shifting task in mice (Parikh et al, 2016). Another study using DA-deficient mice showed similar results in a water U-maze paradigm where mice had to shift from an initially acquired escape strategy to a new strategy (Darvas and Palmiter, 2011).…”

BDNF controls cognitive processes related to neuropsychiatric manifestations via autophagic regulation of p62 and GABAA receptor trafficking

“…The functional link between reduced BDNF signaling and GABA deficits across psychiatric disorders also suggests it may contribute to common behavioral endophenotypes across disorders. Cognitive function is primarily controlled via corticolimbic mechanisms, in part through regulation of excitatory and inhibitory neurotransmission (Kellendonk et al, 2009;Caballero and Tseng, 2016), and a number of synaptic modulators have been implicated in these processes, including BDNF and α5-GABA A R. Notably, reduced expression or activity of BDNF or α5-GABA A R in mice commonly manifests as cognitive inflexibility and sensorimotor gating deficits (Hauser et al, 2005;Engin et al, 2013;Manning and van den Buuse, 2013;Parikh et al, 2016). This suggests these molecules represent a network of regulators underlying cognitive processes commonly affected across psychiatric conditions.…”

“…Bdnf +/mice were recently shown to exhibit reduced cognitive flexibility in a visual discrimination task (Parikh et al, 2016). To further address deficits in cognitive flexibility in Bdnf +/mice, we used a rule shifting paradigm (Bissonette et al, 2008;Cho et al, 2015), in which mice were initially trained to associate food reward with a specific stimulus (i.e., either an odor or a digging medium) and subsequently evaluated for cognitive flexibility by changing the type of stimulus that predicts the reward (Figure 2D).…”

“…We chose these two behavioral endophenotypes since they are relevant to psychiatric manifestations (Kellendonk et al, 2009;Parnaudesu et al, 2013;Swerdlow et al, 2016) and are commonly observed in BDNF mutant mice (Manning et al, 2013;Parikh et al, 2016) and α5-GABA A R-deficient mice (Hauser et al, 2005;Engin et al, 2013). Finally, we analyzed the relevance of the autophagy regulatory pathway to neuropsychiatric manifestations, using gene expression profiles obtained in postmortem brains of MDD and control subjects.…”