Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum

“The ratio of responses to paired afferent stimuli delivered at 50 ms intervals is sensitive to the probability of neurotransmitter release (Zucker, 1989), and an increase this paired-pulse ratio generally signals a decrease in release probability.”

“These striatonigral neurons strongly express D1Rs and generally do not express A2A or D2Rs (Augood and Emson, 1994; Gerfen et al., 1990; Gong et al., 2003).”

“The striatum is the major input nucleus of the basal ganglia, and as such it plays a crucial role in action control and action learning (Saint-Cyr et al., 1995; Graybiel,1998; Lalonde and Botez-Marquard, 1997; Yin and Knowlton, 2006).”

“These striatonigral neurons strongly express D1Rs and generally do not express A2A or D2Rs (Augood and Emson, 1994; Gerfen et al., 1990; Gong et al., 2003).”

“…injection of a local anesthetic, which should inactivate the structure, just prior to a retention test did not impair the ability of the animal to perform a cross-maze task, but just altered the strategy used by the animal from a response-based to a place-based approach (Packard and McGaugh, 1996).”

“Excitotoxic lesions of dorsolateral striatum disrupted habit learning in this study, as previously reported in rat (Hilario et al., 2007; Yin et al., 2004).”

“Dopamine can only act via GPCRs, and thus only modulates striatal neuronal function and synaptic transmission (Richfield et al., 1989; Surmeier et al., 2007).”

“underlying habit memory and motor learning (reviewed by Gubellini et al., 2004; Bonsi et al., 2008; Lovinger, 2010).”

“The phasic dopaminergic activation that drives incentive salience is hypothesized to also engage habit formation and compulsive-like responding for addictive agents via activation of cortical-striatal-pallidal-thalamic loops (90,91).”

“striatal neurons [45–49].”

“…OFC, orbitofrontal cortex; SM, sensorimotor cortex; SN, substantia nigra; VTA, ventral tegmental area; S-O, stimulus-outcome; A-O, actionoutcome; S-R, stimulus-response. excitatory inputs onto MSNs in NAc slices is not DA-dependent (Fields et al., 2007; Lovinger, 2010; Nicola et al., 2000).”

“It has also been shown that the concentration of dopamine , a neuromodulator emitted by dopaminergic cells, controls plasticity processes in various brain areas (Otmakhova and Lisman 1996, Otani et al. 1998, Gurden et al. 2000, Bao et al. 2001, Lovinger 2010).”

“Regulation of striatal glutamate release by DA occurs through inhibition of glutamate release via D 2 DA receptors and CB1 cannabinoid receptors on corticostriatal afferents (Cepeda et al., 2001; Bamford et al., 2004a,b; Lovinger, 2010).”

“It is believed that the interaction between glutamate and striatal activity serves as an important modulator of synaptic plasticity and neural excitability (Surmeier et al., 2007; Kreitzer et al., 2009; Lovinger et al., 2010; Gleich et al., 2015).”

“…neuromodulators In stdP Neuromodulators are involved in most forms of synaptic plasticity ranging from short-term plasticity (ms) (for review see: Lovinger, 2010) to long-term plasticity (hours) (Neuman and Harley, 1983; Frey et al., 1990; Huerta and Lisman, 1993; Thomas et al., 1996), to…”

“Once activated, these receptors facilitate various intracellular signaling mechanisms, which promote both short- and long-lasting cellular responses in developing andmature neurons [49].”

“These morphological changes may reflect complex dynamic alterations due to neurochemical changes with repeated migraine attacks (and perhaps in the interictal period) (see (43)).”

“CB1R signaling is also linked to our finding of DLS dysmorphology by prior work showing that loss of CB1R causes dendritic hypertrophy (40).”

“048 provides presynaptic inhibition of the release of both glutamate and dopamine, a mechanism that contributes to the complexity of striatal function, which has been extensively reviewed elsewhere (Calabresi et al., 2000a, 2000b; Lovinger, 2010).”

“Ac ce pt ed M an us cr ipt important role in recognizing behaviourally significant stimuli (and in error detection) and in regulating goal-directed responses (Lovinger, 2010) and may therefore be particularly important for OCRDs.”

“These include changes in LTD and LTP at excitatory inputs in MSNs (Calabresi et al., 2007; Kreitzer and Malenka, 2008; Lovinger, 2010; Shen et al., 2008), decreased spine density and loss of glutamatergic synapses onto D2 MSNs (Day et al.”

“This region also plays a key role in instrumental learning and habit formation ( Lovinger , 2010 ) .”

“These behavioural treatments might be further enhanced with targeted pharmacotherapy, for which basic data are accruing (Lovinger, 2010).”

“…Teyler, 1989; Jung et al., 1990; Tsumoto, 1990; Kirkwood et al., 1993; Fox, 2002), striatum (Calabresi et al., 1992; Charpier and Deniau, 1997; Lovinger, 2010), ventral tegmental area (Nugent et al., 2007, 2008), cerebellum (Salin et al., 1996; Lev-Ram et al., 2002), and nucleus accumbens…”

“Glutamatergic and dopaminergic afferents modulate each other’s activity while converging on MSN dendritic spines, and GABA release from the MSNs further impacts both glutamate and dopamine release [162, 163].”

“Thus, the functional and morphological changes may reflect complex alterations due to neurochemical changes in thalamo-cortical-basal ganglia activity with repeated migraine attacks (and perhaps in the interictal period) (see [63]).”

“The DMS is involved with goal-directed behaviors, while the DLS is involved with habitual behaviors (Lovinger, 2010; Corbit and Janak, 2016).”

“…and glutamatedopamine pathways (Yamaguchi et al., 2011), and these neurotransmitter systems interact to shape neural excitability and synaptic plasticity in striatal neurons (Di Filippo et al., 2009; Lovinger, 2010; Shiflett and Balleine, 2011; Surmeier et al., 2009) and to regulate behavior.”

“(HFS; Figure 1A) of presynaptic axons is applied in a solution containing low-Mg (< 200 mM) (Jia et al., 2010; Lovinger, 2010), a condition that favors NMDAR activation via the removal of the Mg block (Calabresi et al.”

“Activation of A1 receptors also inhibits excitatory transmission in the striatum [86], while excitatory A2A receptors participate in NMDA receptor dependent long-term potentiation of synapses between cortical pyramidal neurons and principal striatal medium spiny neurons [87, 88].”

“Induction of LTD and LTP requires an intact nigrostriatal projection, and depends upon both dopamine and ionotropic glutamate receptor subtypes involved (Lovinger, 2010).”

“…14 | Article 6 preferentially active in the presence of lower concentrations of dopamine that are more likely to activate high-affinity dopamine type 2 receptors, which will progressively weaken the synaptic strength in those circuits (Grace et al., 2007; Surmeier et al., 2007; Lovinger, 2010).”

“Substantial evidence supports a role for dopamine in mediating reinforcement learning and corticostriatal plasticity, which will not be reviewed here (Montague et al., 1996; Schultz et al., 1997; Reynolds and Wickens, 2002; Schultz, 2002, 2010; Cannon and Palmiter, 2003; Wise, 2004; Berridge, 2007; Goto et al., 2007;…”

“…agents or genetic models of DA neuron degeneration, produces a pronounced motor deficit that closely resembles the motor symptoms characteristic of Parkinson’s disease (Bergman and Deuschl, 2002; Deumens et al., 2002; Lovinger, 2010; Palmiter, 2008; Schultz, 1982; Surmeier et al., 2014).”

“1993; Salamone, 1992; Salamone and Correa, 2012), and in the role of the striatum in acquiring and executing skilled motor patterns (Graybiel, 1998; Hikosaka, 1991; Lacourse et al., 2005; Lovinger, 2010; Salamone, 1992; Yin et al., 2009).”

“Alterations in synaptic plasticity of medium spiny neurons have been linked to functional changes in several contexts (Di Filippo et al., 2009; Surmeier et al., 2009; Lovinger, 2010).”

“Data are expressed as means SEM, and Student’s t test was used for statistical analysis, unless otherwise stated. be obtained in low-magnesium/high-calcium medium (Calabresi et al., 2007; Lovinger, 2010).”

“DA also regulates the plasticity of striatal neurons by modulating glutamatemediated LTD, LTP and synaptic depotentiation [54,55].”

“Dopamine and glutamate signaling interact through multiple cellular mechanisms to shape neural excitability and synaptic plasticity in striatal neurons (Di Filippo et al., 2009; Kreitzer, 2009; Lovinger, 2010; Surmeier et al., 2007).”

“The issue remains controversial and has been addressed in recent excellent reviews (Kreitzer and Malenka, 2008; Surmeier et al., 2009; Lovinger, 2010).”

“LTP at corticostriatal synapses requires proper expression levels and function of NMDARs, D1Rs, A2-type adenosine receptors (A2ARs), and mAChRs (Lovinger, 2010) (Figure 1).”

“Neuromodulation of bidirectional synaptic plasticity in the dorsal striatum is thought to be important to preserve a proper control of habitual behavior”

“The loss of DA in experimental PD causes the impairment of striatal synaptic long-term depression (LTD) in medium spiny neurons (MSNs), suggesting that a critical role of endogenous DA is to enable a form of plasticity representing the possible synaptic correlate of motor memory (Calabresi et al., 1992a,b, 1999, 2007a…”

“This LTD requires postsynaptic co-activation of Group I mGluRs and dopamine D2 receptors and is dependent upon the release endocannabinoids which act as retrograde messengers to suppress presynaptic glutamate release (reviewed in (Lovinger, 2010)).”

“…signaling to cAMP A number of studies demonstrated key roles of neuromodulators acting on distinct GPCRs at discrete points in striatal circuitry in shaping behavioral outcomes related to action selection and reward programming (Castro and Bruchas, 2019; Kravitz and Kreitzer, 2012; Lovinger, 2010).”

“An important feature of Fos-based identification of cocaine ensembles is that only a small fraction of NAc MSNs (2–5”

“Medium spiny GABAergic neurons (MSN), activated by corticostriatal glutamatergic inputs, are the major output neurons for the striatum; these neurons are regulated extensively by the classical neurotransmitters dopamine and acetylcholine (ACh) [1,2,4,6].”

“Although D2 activation is believed to be critical for the induction of synaptic depression (LTD) in D2-expressing MSNs, activation of A2A facilitates potentiation at these synapses (LTP) and A2A blockade prevents this potentiation (Shen et al., 2008; Lovinger, 2010; Peterson et al., 2012).”

“Recent studies have shown that habit formation for natural reward is regulated by striatopallidal neurons of the “indirect pathway” in the basal ganglia circuit (Fuxe et al., 2007; Lovinger, 2010).”

“The striatum consists mostly of GABAergic mediumsized spiny neurons (MSNs), which receive convergent excitatory inputs from cortical and thalamic areas involved in sensorimotor, cognitive and affective functions, and which further project to the output nuclei of the basal ganglia circuitry (Kreitzer, 2009; Lovinger, 2…”

“Finally, severe deficit in procedural learning on the rotarod points towards dorsal striatal (CPu) dysfunction (39, 40).”

“This imbalance of synaptic plasticity has been proposed to be the neurophysiological basis of striatal-dependent learning (reviewed in Lovinger et al., 2010), namely the alterations of long-term depression (LTD) (Kheirbek et al., 2009; Lovinger, 2010).”

“For example, nigral dopaminergic afferents to the dorsolateral striatum participate in habit-learning and automatic responses to cues, while those to the dorsomedial striatum have been implicated in goal-directed behaviors and action selection (Yin and Knowlton, 2006; Wickens et al., 2007; Lovinger, 2010; de Wit et al…”

“Pharmacological studies showed that NMDA, dopaminergic D1 (mainly direct pathway), adenosine A2A (mainly indirect pathway), and muscarinic cholinergic receptors are involved in the induction of LTP (18, 19).”

“…and D2 MSN appear to adapt to low DA concentrations by becoming more sensitive to DA, which is consistent with the general fact that their plastic-ity—a process that enables learning and the formation of habits—is controlled by the level of their stimulation (Sur-meier et al. 2007; Lovinger 2010).”

“This supports existing evidence that cannabinoid-mediated presynaptic inhibition and LTD require some threshold level of synaptic activation that is provided at high cortical frequencies or following prolonged exposure to spontaneous activity (Adermark & Lovinger, 2007; Lovinger, 2010).”

“Conditions for the induction and expression of eCB-mediated synaptic plasticity can vary among circuits and between activity states (for review, see Wilson and Nicoll, 2002; Heifets and Castillo, 2009; Kano et al., 2009; Lovinger, 2010).”

“Dopamine (DA) and glutamate signaling interact in important ways to influence synaptic plasticity at corticostriatal synapses (see [60] [61] [62] for review).”

“Glutamate receptors are involved in the processes of long term potentiation (LTP) and long term depression (LTD) of neuronal firing, which are forms of long term synaptic plasticity critically important for learning [38].”

“Notably, the substrate for the cross-talk between direct and indirect pathways is represented by ECS that induces the LTD of the dorso-striatal MSNs and of their afferent and efferent connections (Lovinger, 2010).”

“The early stages of instrumental learning are modulated by the medial DS, whereas the lateral DS contributes to the later stages of instrumental learning (for review see [76,77]).”

“In contrast to early learning, later expression of automatized responses is thought to be supported by LTD at dorsolateral striatal synapses following metabotropic glutamate and D2 dopamine receptor activation (22, 46).”

“Both LTP and LTD have been identified in DCN local networks (Tzounopoulos et al., 2007).”

“In previous studies, high frequency stimulation has also been shown to induce long-term depression (LTD) of AMPAR EPSCs in MSNs in the striatum (Calabresi et al., 1993; Walsh, 1993; Lovinger, 2010).”

“As presynaptic CB1Rs are key determinants of endocannabinoid‐mediated, long‐term depression (LTD) within the striatum (Lovinger, 2010), it is tempting to speculate that the propensity for LTD at inhibitory SPN–SPN collateral connections or extrastriatal SPN axonal targets is augmented in striosomes.”

“Either repeated paired-pulse stimulation or short-term treatment with an mGluR1/5 agonist (such as DHPG) reliably induces cortico-striatal LTD (for review see Lovinger 2012).”

“The DA neuron cluster in the substantia nigra pars compacta (SNc) projects to the dorsal striatum (caudate and putamen) and coordinates motor responses and participate in action initiation as well as goal-directed (action-outcome) and habitual (stimulus-response) learning (Lovinger, 2010).”

“The functional integrity of the dorsal striatum depends on multiple neurotransmitter systems, including dopaminergic, glutamatergic, and endocannabinoid systems (Lovinger, 2010).”