Responses of nigrostriatal dopamine neurons to high-intensity somatosensory stimulation in the anesthetized monkey

“Primary re-insensitive to aversive stimuli, as they show depressions or activations with slower time courses following pain wards elicit neuronal activations during initial learning periods which decrease progressively and are trans-pinch in anesthetized monkeys (Schultz and Romo, 1987).”

“These studies have shown that noxious stimuli evoke excitation in some DA neurons but inhibition in other DA neurons (Chiodo et al., 1980; Maeda and Mogenson, 1982; Schultz and Romo, 1987; Mantz et al., 1989; Gao et al., 1990; Coizet et al., 2006).”

“In anesthetized animals, dopamine neurons show depressions following painful stimuli (Schultz & Romo 1987, Ungless et al. 2004).”

“We focused on three kinds of neuronal responses: (1) responses elicited by conditioned-stimulus presentation, (2) responses elicited by unconditionedstimulus delivery and (3) responses elicited by unconditioned-stimulus omission.”

“Data from Schultz & Romo 1987. c: Voltammetry of dopamine concentration change following reward-predicting visual-auditory compound stimulus.”

“As described before, midbrain DA neurons displayed specific electrophysiological characteristics (Schultz, 1986; Schultz and Romo, 1987).”

“Aversive stimuli are well known for &30 years to activate 10–50% of dopamine neurons in awake and anesthetized monkeys, rats, and mice (102, 193, 255, 345, 362, 366, 525, 604) and to enhance dopamine concentration in nucleus accumbens (75).”

“…(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).”

“…it with respect to existing electrophysiological experiments on dopamine in aversive situations (Guaracci & Kapp, 1999; Mirenowicz & Schultz, 1996; Schultz & Romo, 1987), which are in mutual disagreement as to the predominant direction and timescale of dopamine responses, and were not designed as…”

“, 2005; Taha and Fields, 2006), also encodes value for negative reinforcement for aversive conditions (Maeda and Mogenson, 1982; Schultz and Romo, 1987; Bassareo et al., 2002; Ungless et al., 2004; Badrinarayan et al., 2012), as well as for pain (Becerra et al.”

“A few dopamine neurons (5–15%) are activated by primary aversive stimuli [26,28,34], which is now confirmed [31,33 ,36,37,38 ,39 ].”

“Aversive stimulation in anaesthetised animals produces varying but often low degrees of mostly slower, activating responses (50% [47]; 18% [48]; 17% [49]; 14% [50]) and often depressions of activity.”

“Although early animal studies indicated that VTA dopaminergic neurons are inhibited by aversive stimuli or unexpected costs (Maeda and Mogenson, 1982; Schultz and Romo, 1987; Tsai et al., 1980; Ungless et al., 2004), more recent studies demonstrate both excitatory and inhibitory responses of dopamine neurons to noxiou…”

“5 spikes/s) in sharp contrast to the highfrequency firing of neurons in the substantia nigra pars reticulata (Schultz and Romo, 1987).”

“…pinch stimuli, electric shock, and stressful events with comparatively slower decreases or increases of impulse activity (Chiodo and others 1979; Schultz and Romo 1987) or increases in striatal dopamine release (Louilot and others 1986; Abercrombie and others 1989; Doherty and Gratton 1992;…”

“…primary aversive stimuli lack positive reinforcing functions but induce attention, and dopamine neurons respond only rarely with the typical phasic activations (Mirenowicz and Schultz, 1996), although they show depressions or occasional activations at a slower time scale (Schultz and Romo, 1987).”

“However , it has been well docu - mented that DA neurons show phasic activations by a wide vari - ety of salient stimuli , including novel and high - intensity stimuli ( Jacobs , 1986 ; Schultz and Romo , 1987 ; Ljungberg et al .”

“Therefore, we must initial positive component or may be followed by a prolonged posi- specify the form of function in terms of x in order to represent the tive component (Schultz and Romo, 1987).”

“Initially, extracellular increases in dopamine concentration in VTA projection targets were difficult to reconcile, as most studies had shown a suppression of VTA dopamine neuronal firing during stress or aversive stimulus presentation (Guarraci and Kapp 1999; Mantz et al. 1989; Mirenowicz and Schultz 1996; Schultz an…”

“Indeed, several studies (Maeda and Mogenson, 1982; Schultz and Romo, 1987; Tsai et al., 1980; Ungless et al., 2004), including our own (Coizet et al., 2006), now show that noxious stimuli cause a phasic suppression of DA neuronal activity.”

“An IS break was commonly observed in prior studies where the dopaminergic identity of selected neurons was confirmed by apomorphine injection (Figures 3F and 3G) (Guyenet and Aghajanian, 1978; Schultz and Romo, 1987).”

“Consistent with this idea, self-stimulation of the striosomes, but not the matrix, leads to rapid response acquisition (White & Hiroi, 1998), suggesting that Schultz & Romo, 1987).”

“However, earlier studies (Schultz and Romo, 1987) as well as more recent studies, showed heterogeneities among dopamine neurons (Bromberg-Martin et al., 2010).”

“For example, a single noxious stimulus, such as a footshock delivered in anaesthetized animals, has been shown to induce a transient decrease of DA neuron firing rate [58–60], and in some cases an increase [59,61].”

“However, to date electrophysiological studies have not shown a response to stress that is consistent with these neurochemical measures; thus, upon exposure to a brief noxious stimulus, DA neurons exhibit a transient inhibition in firing (Schultz and Romo, 1987; Grace, 2000; Ungless et al., 2004) and, in a minority of…”

“The association between mesolimbic circuitry and neural substrates of pain and analgesia has been considered in past decades [29,37,53]; for noxious or aversive conditions, both excitatory and inhibitory responses of dopaminergic neurons have been observed [16,23,43,50,62,68], both increases and decreases in extracell…”

“[19], followed by ourselves [20,21] and confirmed by others [22–25], subsets of dopamine neurones are activated by airpuffs and loud tones.”

“Extracellular spikes may have an initial positive component or may be followed by prolonged positive component (Schultz and Romo 1987).”

“These results verified that the lentiviral vectors expressing shRNA specific for D1R and D2R selectively and sufficiently suppressed their target RNAs and down-regulated the amount of the respective protein products.”

“…that dopamine neurons are universally inhibited by aversive stimuli (Ungless et al., 2004), others report both inhibition and excitation (Chiodo et al., 1980; Schultz and Romo, 1987; Mantz et al., 1989; Guarraci and Kapp, 1999; Coizet et al., 2006; Matsumoto and Hikosaka, 2009; Tan et al., 2012).”

“These findings imply that the stimulus-locked DA responses are not uniquely dictated by the physical parameters of the stimulus (28) but instead are related to the monkey’s subjective percept of intensity or saliency.”

“…studies have reported that dopamine neurons are activated by aversive stimuli both in anesthetized (Brischoux et al., 2009; Coizet et al., 2006; Schultz and Romo, 1987) and awake animals (Guarraci and Kapp, 1999; Joshua et al., 2008; Matsumoto and Hikosaka, 2009), although the proportions and…”

“Several studies have demonstrated that subsets of dopamine neurons are activated by threatening or noxious stimuli (Brischoux et al., 2009; Chiodo et al., 1979; Mantz et al., 1989; Schultz and Romo, 1987; Wang and Tsien, 2011), as well as threat-predictive stimuli following fear conditioning (Gore et al.”

“Importantly, our finding that inhibition is not the default response of dopaminergic SN neurons to aversive stimuli mirrors previous work in monkeys (Schultz and Romo, 1987; Joshua et al., 2008).”

“…et al., 1997; Schultz, 1998; Horvitz, 2000; Dommett et al., 2005) and that a minority of dopamine neurons can be activated by aversive stimuli (Schultz and Romo, 1987; Mirenowicz and Schultz, 1996; Guarraci and Kapp, 1999; Coizet et al., 2006; Joshua et al., 2008; Brischoux et al., 2009;…”

“Dopamine neurons are known to respond to visual stimuli that precede and predict reward delivery and to motor acts such as bar release that lead to a forthcoming reward (Schultz and Romo, 1987).”

“1A) and low basal firing rates (0.1–15.0 Hz) (Schultz and Romo, 1987).”

“Although previous studies suggest that stress does not increase the firing rate of nigrostriatal DA neurons, those studies were conducted in anesthetized animals (Schultz and Romo, 1987) or compared the firing rate of' DA neurons during stress to the firing rate during an active waking state (Strecker and Jacobs, 1985…”

“Conversely, the omission of an expected reward, along with punishments, are associated with a depression in the activity of the dopaminergic neurons, thus resulting in a dip in tonic dopamine levels (Schultz & Romo, 1987; Mirenowicz & Schultz, 1996; Matsumoto & Hikosaka, 2009; Hart et al. 2014).”

“0 Hz), as previously described (Schultz and Romo, 1987).”

“We previously found that 1DR task gave rise to a strong behavioral bias: saccade latency was shorter and saccade velocity was higher when the saccade was followed by a reward (rewarded condition) than when it was followed by no reward (unrewarded condition) (Takikawa et al. 2002).”

“However, the implied stress-induced increase in neostriatal dopamine release is inconsistent with electrophysiolgical data indicating that the firing rate of nigrostriatal dopamine neurons is not increased by exposure to stress (Schultz and Romo, 1987; Strecker and Jacobs, 1985).”

“Dopaminergic nigrostriatal neurons were found to be activated by noxious stimulation (Schultz and Romo, 1987), lesions of nigrostriatal neurons enhanced nociception (Carey, 1986; Lin et al.”

“Likewise, deep pentobarbital anesthesia suppresses nearly all burstfiring activity of DA neurons in monkeys (Schultz and Romo, 1987).”

“…ideally be tested with unit recordings of DA neurons in aversive paradigms; the very sparse and problematic set of such recordings so far available reveals some DA neurons with excitatory and some with inhibitory responses (Schultz & Romo, 1987; Mirenowicz & Schultz, 1996; Guarraci & Kapp, 1999).”

“Dopamine neurons are activated by aversive stimuli (Tsai et al., 1980; Schultz and Romo, 1987; Mirenowicz and Schultz, 1996; Guarraci and Kapp, 1999).”

“…receive information fromprefrontal, insular, and thalamic areas, and send dopaminergic projections to the ventral tegmentum, substantia nigra, and globus pallidus (Avendano et al., 2006; DeVito et al., 1980; Ferry et al., 2000; Gorbachevskaya, 1997; Saper, 1982; Schultz and Romo, 1987).”

“Aversive stimulation in anaesthetised animals produces varying but often low degrees of mostly slower, activating responses (50% [12], 18% [13], 17% [14], 14% [15]).”

“2 ms were considered as potential DA units (Grace and Bunney, 1984; Kim et al., 2016; Schultz and Romo, 1987).”

“Noxious stimuli consistently excite DA neurons located in the dorsolateral part of the substantia nigra pars compacta, which projects to the dorsolateral striatum or the tail of the striatum (Lerner et al., 2015; Matsumoto and Hikosaka, 2009; Menegas et al., 2017; Schultz and Romo, 1987).”

“Electrophysiological experiments have shown that electrical or natural stimulation of the skin nociceptors modifies the spontaneous activity of the dopamine neurons of the SNc (Gao et al. 1990; Schultz and Romo 1987).”

“…VP, leading several studies to categorize neurons on the basis of their responses to primary rewards and cues that predict them (Ahrens et al., 2016; Ito and Doya, 2009; Ottenheimer et al., 2018; Richard et al., 2016, 2018; Smith et al., 2009; Tachibana and Hikosaka, 2012; Tindell et al., 2004).”