Firing patterns of serotonin neurons underlying cognitive flexibility

Abstract

Serotonin is implicated in mood and affective disorders 1,2 but growing evidence suggests that its core endogenous role may be to promote flexible adaptation to changes in the causal structure of the environment 3-8 . This stems from two functions of endogenous serotonin activation: inhibiting learned responses that are not currently adaptive 9,10 and driving plasticity to reconfigure them 11-13 . These mirror dual functions of dopamine in invigorating reward-related responses 14,15 and promoting plasticity that reinforces new ones 16,17 . However, while dopamine neurons are known to be activated by reward prediction errors 18,19 , consistent with theories of reinforcement learning 18,20 , the reported firing patterns of serotonin neurons 21-23 do not accord with any existing theories 1,24,25 . Here, we used long-term photometric recordings in mice to study a genetically-defined population of dorsal raphe serotonin neurons whose activity we could link to normal reversal learning. We found that these neurons are activated by both positive and negative prediction errors, thus reporting the kind of surprise signal proposed to promote learning in conditions of uncertainty 26,27 . Furthermore, by comparing cue responses of serotonin and dopamine neurons we found differences in learning rates that could explain the importance of serotonin in inhibiting perseverative responding. Together, these findings show how the firing patterns of serotonin neurons support a role in cognitive flexibility and suggest a revised model of dopamine-serotonin opponency with potential clinical implications.

Transient inhibition and long-term facilitation of locomotion by phasic optogenetic activation of serotonin neurons

“…A second set of ideas posits a signal that modulates the cost of acting (or not-acting) itself ( Miyazaki et al, 2014 ; Fonseca et al, 2015 ; Meyniel et al, 2016 ). A third set of ideas is related to the signaling of uncertainty, either in predicting events or the outcomes of ones own actions ( Maswood et al, 1998 ; Amat et al, 2005 ; Matias et al., 2016 ). Uncertainty-related signals may be more complex to interpret as they could bias benefits and costs toward either action or inaction depending on the shape of the value landscape or could shift the balance between different behavioral control systems ( Daw et al, 2005 ).…”

“…Our data are consistent with opponent effects of 5-HT and DA as modulators of action vigor, but not as reinforcement learning signals. Simultaneous or parallel recordings from multiple neuromodulator systems will be important for resolving the interplay between these systems ( Cohen et al, 2012 , 2015 ; Matias et al., 2016 ). An additional complexity is that, due to differences in receptor kinetics, phasic firing and tonic firing of 5-HT neurons may convey different signals ( Daw et al, 2002 ; Cools et al, 2011 ; Cohen et al, 2015 ).…”

Behavior Variability of a Conditional Gene Knockout Mouse as a Measure of Subtle Phenotypic Trait Expression. The Case of Mouse Executive Function Distortion

“…For the calculus details see ST2-1, ST2-2, ST4-1 and ST4-2.! thalamus, neocortex layers (4)(5), lateral EC layer 2 hypothalamus, neocortex layers (2)(3)(4)6), Fig.4. For the calculus details see Fig.2, ST2-1, ST2-2, ST4-1, ST4-2, ST5-1, and ST5-2.…”

“…A. Exon-intron composition of mouse Ntng1 with the removed part dash-outlined, see(22) for the details of each construct design. (B-E, outmost left and right) Mice performance over the spatials(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) presented by four behavioral parameters. The dashed line separating spatials (2-7) and(8)(9)(10)(11)(12)(13) indicates the data split on the low cognitive demand (LCD) and high cognitive demand (HCD) sessions.…”

Slow motion

“…Finally, the interpretation of optogenetic stimulation experiments requires some caution. Techniques such as optogenetic tagging ( Cohen et al, 2015 ; Li et al, 2016 ; Liu et al, 2014 ) and fiber fluorometry ( Matias et al, 2016 ; Li et al, 2016 ) have begun to provide data on the activity of specific serotonin neurons. These experiments generally find diverse firing patterns in serotonin neurons.…”