Does phasic dopamine release cause policy updates?

Phasic dopamine activity is believed to both encode reward-prediction errors (RPEs) and to cause the adaptations that these errors engender. If so, a rat working for optogenetic stimulation of dopamine neurons will repeatedly update its policy and/or action values, thus iteratively increasing its work rate. Here, we challenge this view by demonstrating stable, non-maximal work rates in the face of repeated optogenetic stimulation of midbrain dopamine neurons. Furthermore, we show that rats learn to discriminate between world states distinguished only by their history of dopamine activation. Comparison of these results to reinforcement learning simulations suggests that the induced dopamine transients acted more as rewards than RPEs. However, pursuit of dopaminergic stimulation drifted upwards over a time scale of days and weeks, despite its stability within trials. To reconcile the results with prior findings, we consider multiple roles for dopamine signalling.

Ovariectomy reduces cholinergic modulation of excitatory synaptic transmission in the rat entorhinal cortex.

Estrogens are thought to contribute to cognitive function in part by promoting the function of basal forebrain cholinergic neurons that project to the hippocampus and cortical regions including the entorhinal cortex. Reductions in estrogens may alter cognition by reducing the function of cholinergic inputs to both the hippocampus and entorhinal cortex. In the present study, we assessed the effects of ovariectomy on proteins associated with cholinergic synapses in the entorhinal cortex. Ovariectomy was conducted at PD63, and tissue was obtained on PD84 to 89 to quantify changes in the degradative enzyme acetylcholinesterase, the vesicular acetylcholine transporter, and muscarinic M1 receptor protein. Although the vesicular acetylcholine transporter was unaffected, ovariectomy reduced both acetylcholinesterase and M1 receptor protein, and these reductions were prevented by chronic replacement of 17ß-estradiol following ovariectomy. We also assessed the effects of ovariectomy on the cholinergic modulation of excitatory transmission, by comparing the effects of the acetylcholinesterase inhibitor eserine on evoked excitatory synaptic field potentials in brain slices obtained from intact rats, and from ovariectomized rats with or without 17ß-estradiol replacement. Eserine is known to prolong the effects of endogenously released acetylcholine, resulting in an M1-like mediated reduction of glutamate release at excitatory synapses. The reduction in excitatory synaptic potentials in layer II of the entorhinal cortex induced by 15-min application of 10 µM eserine was greatly reduced in slices from ovariectomized rats as compared to intact rats and ovariectomized rats with replacement of 17ß-estradiol. The reduced modulatory effect of eserine is consistent with the observed changes in cholinergic proteins, and suggests that reductions in 17ß-estradiol following ovariectomy lead to impaired cholinergic function within the entorhinal cortex.

The trade-off between pulse duration and power in optical excitation of midbrain dopamine neurons approximates Bloch's law.

Optogenetic experiments reveal functional roles of specific neurons. However, functional inferences have been limited by widespread adoption of a restricted set of stimulation parameters. Broader exploration of the parameter space can deepen insight into the mapping between selective neural activity and behavior. In this way, characteristics of the activated neural circuit, such as temporal integration, can be inferred. Our objective was to determine whether an equal-energy principle accounts for the interaction of pulse duration and optical power in optogenetic excitation. Six male TH::Cre rats worked for optogenetic (ChannelRhodopsin-2) stimulation of VTA dopamine neurons. We used a within-subject design to describe the trade-off between pulse duration and optical power in determining reward seeking. Parameters were customized for each subject based on behavioral effectiveness. Within a useful range of powers (~12.6-31.6 mW) the product of optical power and pulse duration required to produce a given level of reward seeking was roughly constant. Such reciprocity is consistent with Bloch's law, which posits an equal-energy principle of temporal summation over short durations in human vision. The trade-off between pulse duration and power broke down at higher powers. Thus, optical power and duration can be adjusted reciprocally for brief durations and lower powers, and power can be substituted for pulse duration to scale the region of excitation in behavioral optogenetic experiments. The findings demonstrate the utility of within-subject and trade-off designs in optogenetics and of parameter adjustment based on functional endpoints instead of physical properties of the stimulation.

Serotonin 5-HT1A Receptor-Mediated Reduction of Excitatory Synaptic Transmission in Layers II/III of the Parasubiculum.

Serotonin (5-HT) has important effects on cognitive function within the hippocampal region where it modulates membrane potential and excitatory and inhibitory synaptic transmission. Here, we investigated how 5-HT modulates excitatory synaptic strength in layers II/III of the parasubiculum in rat brain slices. Bath-application of 1 or 10 µM 5-HT resulted in a strong, dose-dependent, and reversible reduction in the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded in the parasubiculum. The 5-HT reuptake blocker citalopram (10 µM) also reduced fEPSP amplitudes, indicating that 5-HT released within the slice inhibits synaptic transmission. The reduction of fEPSPs induced by 5-HT was blocked by the 5-HT1A receptor blocker NAN-190 (10 µM), but not by the 5-HT7 receptor blocker SB-269970 (10 µM). Moreover, the 5-HT1A agonist 8-OH-DPAT induced a reduction of fEPSP amplitude similar to that induced by 5-HT. The reduction was prevented by the 5-HT1A receptor blocker NAN-190. The reduction in fEPSPs induced by either 5-HT or by 8-OH-DPAT was accompanied by an increase in paired-pulse ratio, suggesting that it is due mainly to reduced glutamate release. Our data suggest that the effects of serotonin on cognitive function may depend in part upon a 5-HT1A-mediated reduction of excitatory synaptic transmission in the parasubiculum. This may also affect synaptic processing in the entorhinal cortex, which receives the major output projection of the parasubiculum.