Responses of midbrain dopamine neurons to behavioral trigger stimuli in the monkey

“…measurements of DA neuron activity, because these studies have only been able to distinguish between DA and non-DA neurons by using indirect methods, based on neural properties such as firing rate, spikewaveform, and sensitivity to D2 receptor agonists (Grace and Bunney, 1983; Schultz, 1986).”

“, neurons (Schultz, 1986; Schultz et al., 1997; Schultz and Romo, 1990).”

“Because of the stereotyped character of phasic responses of DA neurons to external stimuli seen before (Schultz, 1986; Romo and Schultz, 1990; Schultz and Romo, 1990) a standard time window procedure was developed in order to quantify and compare objectively the neuronal responses between different parts of experiment…”

“…be correincreased in nonhuman primates early in the acquisition lated with this motion, the absence of brain regions of lever pressing behavior (Schultz, 1986; Nishino et al., with time course changes specific for cocaine-induced 1987; Romo and Schultz, 1990; Schultz and Romo, 1990; craving is…”

“…(A9), and adjoining groups A8 and A 10, discharged initially negative or positive impulses at low frequencies (0.5-7.0 imp/s) and with polyphasic waveforms of relatively long durations ( 1.8-5.0 ms), in agreement with previous experience (Romo and Schultz 1990; Schultz 1986; Schultz and Romo 1987).”

“By contrast, Schultz and his colleagues (Ljungberg et al., 1992; Schultz et al., 1993) report that the responses ofthe dopamine-containing neurons , once acquired, progressively diminish with overtraining.”

“It is tempting to speculate that this local mechanism acts at a much slower timescale [43,155], and potentially at timepoints during a trial in which dopamine neurons are not phasically activated, such as during delay periods of a task.”

“stimuli have been shown to phasically stimulate the neuronal activity of midbrain DA neurons by enhancing their bursting mode (Schultz, 1986), and bursting activity results in a more pronounced and plausibly more efficacious neurotransmitter release at the terminal region (Gonon, 1988).”

“The irregular firing of ventral tegmental area (VTA) neurons changes to a high-frequency burst pattern in response to rewardpredicting stimuli and novelty (Schultz, 1986, 1998; Hyland et al., 2002).”

“One limitation in the above electrophysiological studies is that the identification of dopamine neurons was based on indirect physiological properties such as wide spike waveforms (Grace & Bunney 1983, Schultz 1986, Ungless & Grace 2012).”

“Certainly, the touch of a piece of apple is a learned reinforcer for Schultz’s very well trained monkeys (Schultz 1986), as, it would appear, are the click or sight of the opening door behind which food is to be found (Schultz 1986).”

“…action potential Ͻ1 ms in duration, which represents the minimum cutoff between DA and slow-firing non-DA cells in recordings with the filter settings commonly used in recordings from conscious rats and monkeys (Schultz, 1986; Romo and Schultz, 1990; Ljungberg et al., 1992; Hyland et al., 2002).”

“The latter initially interpreted the control of phasic firing in VTA as supporting “behavioral activation” [86] and “motivational arousal” [89].”

“Given that the geometry of dendritic and axonal processes in the dorsal raphe is diverse, with fusiform, multipolar, and ovoid somata (Diaz-Cintra et al., 1981), it is potentially difficult to optimize the location of electrode tip relative to cell bodies across the population (cf. Schultz, 1986).”

“Dopamine neurons consistently fail to show major covariations with movements (DeLong and others 1983; Schultz and others 1983; Schultz 1986).”

“In ambulatory animals, VTA neurons discharge with bursts of spikes, a pattern which releases more DA than does evenly spaced discharges (Gonon and Buda, 1985; Schultz, 1986).”

“In accordance with previous studies on the discharge properties of dopamine neurons (Grace and Bunney, 1983; Schultz, 1986), we identified dopamine neurons on the basis of the following four criteria.”

“75 The short-latency response of dopamine neurons to primary rewards and conditioned, reward-predicting stimuli 42,46,60,62,66 might constitute a biological implementation of a TD reinforcement signal.”

“Dopaminergic neurons in the mesencephalon can be activated both by primary food and fluid rewards and by conditioned incentive stimuli predicting reward (Schultz, 1986; Romo and Schultz, 1990; Ljungberg et al., 1992).”

“Instead, midbrain DA neurons are activated specifically in situations with a reward value, whether elicited by conditioned or unconditioned stimuli (Schultz, 1986; Nishino et al., 1987; Romo and Schultz, 1990; Ljungberg etal., 1991).”

“F or p er so na l u se o nl y. phasic activity neurons around behavioral transitions (Schultz 1986, Jin & Costa 2010), dopamine neurons have been shown to be phasically activated by both appetitive and aversive events, responding in a way that reflects the salience but not the value of the events…”

“However, it is consistent with the paucity of movement-related activity in dopamine cells in monkeys [15–19], rats [20 ,21,22], or cats [23], and imaging studies in humans that indicate responses to reward in the striatum [24–26].”

“Low-frequency, asynchronous firing patterns were used to simulate tonic firing, with neurons firing independently of each other at an average rate of 5 Hz (Grace and Bunney 1984; Schultz 1986 ).”

“Thus, endogenous stimulation of VR1 could be implicated in motivation and reward mechanisms linked to the dopaminergic system (Schultz, 1986; Mirenowicz and Schultz, 1996).”

“Slower electrophysiological dopamine changes occur with movements (Schultz et al. 1983; Schultz 1986; Romo and Schultz 1990), but are sluggish and inconsistent and often fail to occur in better controlled behavioral tasks (DeLong et al. 1983; Schultz and Romo 1990; Ljungberg et al. 1992; Waelti et…”

“In particular, mesostriatal dopaminergic neurons signal reward-predicting stimuli and receipt of unpredicted rewards by brief bursts of high-frequency neuron activity (Schultz, 1986, 2002).”

“Interestingly, a burst of action potentials is capable of releasing more DA in specific projection areas than the same number of spikes organized in spaced action potentials do (Schultz, 1986).”

“We investigated whether mAChR regulation of DA signaling varies with presynaptic activity and identified the mAChRs responsible in sensorimotor- versus limbic-associated striatum.”

“…trained in an operant task detect some dopaminergic VTA neurons that encode discrepancies between a predicted outcome, such as a juice reward normally delivered following a conditioned stimulus, and the reward’s actual occurrence (Schultz 1986; Romo and Schultz 1990; Schultz et al. 1993).”

“Durations of 1 ms represent the typical cutoff between DA and slow-firing non-DA cells under these recording conditions in both rats and monkeys (Schultz, 1986; Romo and Schultz, 1990; Ljungberg et al., 1992; Hyland et al., 2002).”

“These neurons seem to essentially capture the properties of the δ-signal in TD learning (Miller et al. 1981; Schultz 1986; Mirenowicz and Schultz 1994; Hollerman and Schultz 1998 for reviews see Schultz 1998; Schultz and Dickinson 2000; Schultz 2002, but see Redgrave et al. 1999).”

“Ethanol also inhibited up-states evoked by brief electrical stimulation of the VTA designed to mimic the in vivo bursting pattern of DA neurons upon presentation of rewarding stimuli (Schultz, 1986; Bayer et al., 2007).”

“Left: In this model, phasic DA release is proposed to occur as a result of a behaviorally relevant stimulus causing DA cells to emit a burst of spikes (Schultz 1986).”

“The switch in firing mode of mesostriatal DA neurons, from low to higher firing frequencies, is thought to encode information about the prediction and receipt of reward or behaviorally salient stimuli (Schultz, 1986, 2002; Morris et al., 2004; Matsumoto and Hikosaka, 2009).”

“However, once the behavioral act is acquired, the DA system no longer responds to the learned stimulus event (Schultz, 1986; Schultz and Romo, 1990).”

“Using methods described previously (Schultz 1986), extracellular activity was recorded with moveable microelectrodes from single neurons in the left striatum of two Macaca fascicularis monkeys during contralateral performance of a delayed go-nogo task.”

“Dopamine (DA) neurons arising from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) contribute during the formation of rewarded behaviors (Bayer and Glimcher, 2005; Schultz, 1986, 1998).”

“The time course of maximal autoinhibition appears to be suitable to enhance the DA signal in response to " meaningful " burst firing (Schultz, 1986), as opposed to baseline firing of substantia nigra neurons.”

“…such as the dopaminergic midbrain or orbitofrontal cortex (OFC), where neurons respond directly to the reinforcing properties of food or money (Schultz, 1986; Critchley and Rolls, 1996; O’Doherty et al., 2001), and on the structures such as the striatum or anterior cortex, where neuronal…”

“Although the DA neurons that project to the prefrontal cortex may have higher discharge rates (Chiodo et al., 1984; Lammel et al., 2008), many midbrain DA neurons often exhibit similar overall firing properties (Schultz, 1986; Clark and Chiodo, 1988; Gariano et al., 1989; Robinson et al., 2004).”

“Although lesions of the nigrostriatal dopamine system lead to severe akinesia (Poirier 1960; Schultz et al. 1985), we found that dopamine neurons showed no comparable premovement activation in either of the tasks used presently (Romo and Schultz 1986, and unpublished) while responding well to trigger stimuli ( Schultz…”

“have helped explain how the firing rate of dopamine neurons is coded within the midbrain (Schultz et al., 1997; Schultz, 1996; Mirenowicz & Schultz, 1994; Schultz, Apicella, & Ljungberg, 1993; Ljungberg, Apicella, & Schultz, 1992; Romo & Schultz, 1990; Schultz, 1986).”

“During large arm reaching movements toward food boxes, which engage a large proportion of arm and eye muscles in monkeys, select subpopulations of dopamine neurones are activated (31–44%) or depressed (15–17%) [50,51] (Figure 2a,b), sometimes distinguishing between contraand ipsilateral reaching [50].”

“The biphasic, time-locked changes in NAcc DA transmission suggested by our data, although unexpected, are nonetheless congruent with electrophysiological evidence that similar changes in VTA DA cell activity are associated with food reinforcement ( Schultz, 1986; Nishino et al., 1987; Romo and Schultz, 1990; Schultz a…”

“These features are similar to those used previously to characterize DA neurons in the monkey SNc (Schultz, 1986 ), suggesting that both update-and sustain-type neurons were dopaminergic.”

“Dopamine neurons in the substantia nigra of monkeys respond to trigger stimuli for behavioral reactions ( Schultz 1986b ).”

“Identification of the substantia nigra through the thalamus was described originally by Schultz (1986).”