Abstract
Synapses in the cerebral cortex constantly change and this dynamic property regulated by the action of neuromodulators such as dopamine (DA), is essential for reward learning and memory. DA modulates spike-timing-dependent plasticity (STDP), a cellular model of learning and memory, in juvenile rodent cortical neurons. However, it is unknown whether this neuromodulation also occurs at excitatory synapses of cortical neurons in mature adult mice or in humans. Cortical layer V pyramidal neurons were recorded with whole cell patch clamp electrophysiology and an extracellular stimulating electrode was used to induce STDP. DA was either bath-applied or optogenetically released in slices from mice. Classical STDP induction protocols triggered non-hebbian excitatory synaptic depression in the mouse or no plasticity at human cortical synapses. DA reverted long term synaptic depression to baseline in mouse via dopamine 2 type receptors or elicited long term synaptic potentiation in human cortical synapses. Furthermore, when DA was applied during an STDP protocol it depressed presynaptic inhibition in the mouse but not in the human cortex. Thus, DA modulates excitatory synaptic plasticity differently in human vs. mouse cortex. The data strengthens the importance of DA in gating cognition in humans, and may inform on therapeutic interventions to recover brain function from diseases.
Highlights
Humans and other mammalians are characterized by their ability to produce goal-directed and intelligent behaviors beyond simple stimulus–response associations
We found that the τ = + 10 ms spike-timing-dependent plasticity (STDP) induction protocol elicited timing-dependent long-term depression (t-LTD) for rising slope (Figure 4, control data, 78.7 ± 7.4, vs. 100%, p = 0.02, n = 7) and peak amplitude (Supplementary Figure 7, control data) of EPSPs recorded from layer 5 pyramidal neurons
We observed a non-hebbian t-LTD triggered by one post-synaptic AP preceded by pre-synaptic spiking by 10 ms ( τ = + 10 ms) evoked by extracellular stimulation with intact synaptic inhibition in layer 5 pyramidal neurons of the neocortex from mature adult mice in vitro
Summary
Humans and other mammalians are characterized by their ability to produce goal-directed and intelligent behaviors beyond simple stimulus–response associations. It is believed that the neuromodulator dopamine (DA) plays a key role in gating cortical operations underlying cognitive functions, such as working memory (Arnsten et al, 2012), attention (Thiele and Bellgrove, 2018), and flexible behavior (Klanker et al, 2013). The gating elicited by DA, released by midbrain axonal varicosities and terminal endings within the cerebral cortex, is assumed to represent a key molecular substrate underlying cognitive performance including stimulus selection, working memory, rule switching and decision making (Merten and Nieder, 2012). Many theories have been proposed to account for by DA circuit mechanisms underlying cortical-mediated executive control (Ott and Nieder, 2019). One of the most successful is the reward prediction error theory and its experimental demonstration in DA neurons (Schultz et al, 1997)
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