Biochemical computation underlying behavioral decision-making

Abstract

7Computations in the brain are broadly assumed to emerge from patterns of fast electrical 8 activity. Challenging this view, we show that a male fly's decision to persist in mating, 9 even through a potentially lethal threat, hinges on biochemical computations that enable 10 processing over minutes to hours. Each neuron in a recurrent network measuring time 11 into mating contains slightly different internal molecular estimates of elapsed time. 12Protein Kinase A (PKA) activity contrasts this internal measurement with input from the 13 other neurons to represent evidence that the network's goal has been achieved. When 14 consensus is reached, PKA pushes the network toward a large-scale and synchronized 15 burst of calcium influx, which we call an eruption. The eruption functions like an action 16 potential at the level of the network, transforming deliberation within the network into an 17 all-or-nothing output, after which the male will no longer sacrifice his life to continue 18 mating. We detail the continuous transformation between interwoven molecular and 19 electrical information over long timescales in this system, showing how biochemical 20 activity, invisible to most large scale recording techniques, is the key computational 21 currency directing a life-or-death decision. 22 23 24 25 32 33A fundamental problem in neural computation stems from the need for neurons within a 34 network to communicate without triggering premature responses in downstream 35 circuitry 1-3 . This problem is compounded when the computations are performed over 36 long timescales, as in many decision-making paradigms 4 . In single neurons, the action 37 potential solves an analogous problem by transforming accumulated positive and 38 negative inputs into a transient, all-or-nothing output that is broadcasted to postsynaptic 39 targets. Here we identify a similar mechanism acting at the network level and over 40 timescales ranging from seconds to hours, which we call an eruption. 42The Corazonin-expressing (Crz) neurons of the male abdominal ganglion comprise an 43 exceptionally tractable system for investigating neuronal networks and behavioral 44 control. These four neurons drive two simultaneous and crucial events in the lives of the 45 male and his mating partner: i) the transfer of sperm from the male to the female 5 and ii) 46 a transition out of a period of insurmountably high motivation to continue mating 6 . Both of 47 these events occur six minutes after a mating begins and are under the control of a 48 molecular timer encoded by the slowly-decaying autophosphorylation of the kinase 49 CaMKII 6 . We show that the Crz neurons use cyclic AMP (cAMP) signaling to average 50 evidence about the passage of time across the network and generate an eruption that 51 signals to downstream circuitry only when a consensus is reached. In addition to 52 revealing a new network phenomenon, these results explain the function of CaMKII in 53 the only mechanism for interval timing yet to be described. 55 RESULTS 57The Crz neurons form a recu...