Dissociable Effects of Lesions to Orbitofrontal Cortex Subregions on Impulsive Choice in the Rat

“Coronal sections (60 m) were stained with cresyl violet and lesion locations were mapped onto standardized sections of the rat brain (Paxinos and Watson, 1998).”

“Preferential activation of mOFC is associated with choice of immediate primary or conditioned reinforcers relative to delayed ones (McClure et al., 2004, 2007) and correlates positively with individual differences in preference for smaller–immediate rewards on a delay-discounting task (Hariri et…”

“In primates, medial OFC (mOFC) has been associated with responding to, monitoring, or adjusting the incentive value of stimuli, whereas lateral OFC (lOFC) has been implicated in punishment or suppression of previously rewarded responses following contingency change (Iversen and Mishkin, 1970; Elliott et al., 2000; O’D…”

“OFC damage in humans leads to increased impulsivity, which may result from bias toward immediate rewards (Bechara et al., 2000; Berlin et al., 2004).”

“…nonhuman primates shows that caudal lOFC has dense interconnections with NAc core, ventral tegmental area (VTA), and BLA, whereas mOFC has dense reciprocal connections with the hippocampus and only weak connectivity with NAc core, VTA, and BLA (Morecraft et al., 1992; Carmichael and Price, 1995).”

“…and/or responses that lead to immediate feedback of reward (Elliott et al., 2000; O’Doherty et al., 2001) and bias stimulus-driven, behavioral responses toward immediate goals (McClure et al., 2004, 2007). mOFC damage could disrupt such bias, shifting responding toward larger– delayed options.”

“The orbitofrontal cortex (OFC) has been strongly implicated in reinforcement-guided decision making (Murray et al., 2007; Wallis, 2007; Doya, 2008).”

“Other researchers have hypothesized that mOFC may be better conceived as an integration site for subjective goal value signals (Kable and Glimcher, 2009), facilitating comparison of choice-options varying in parameters such as delay, magnitude, and probability.”

“, 2008; Young and Shapiro, 2009) and spatially cued operant responses (Boulougouris et al., 2007; Mar et al., 2011).”

“The basolateral amygdala and the hippocampus, as well as the lateral orbitofrontal cortex (lateral OFC) and medial OFC (mOFC) — but not the medial PFC 17 — have considerable modulatory effects on delay discounting 52–60 .”

“In the light of clinical evidence (6, 9), we asked whether we could restore the striatal inhibition by optogenetically altering lOFC input to the striatum.”

“…to designate the “parts” of prefrontal cortex across species: namely, by outlining behavioral, neurochemical, and electrophysiological properties (Markowitsch and Pritzel, 1979), and by studying phylogenetic (Passingham and Wise, 2012) and ontogenetic relationships (Goldman, 1971) of these…”

“…2007; Rolls and Grabenhorst, 2008; Rudebeck and Murray, 2008; Burke et al., 2009; Schoenbaum et al., 2009; Noonan et al., 2010; Walton et al., 2010; Mar et al., 2011), all of which reflect a compromise in the relative potency of explicitly imagined outcomes, as opposed to routine habits, in…”

“Mar et al. (2011)”

“Studies in the past decade have found considerable anatomical (Groenewegen and Uylings, 2010; Hoover and Vertes, 2011; Vertes, 2004) and functional heterogeneity within the PFC and OFC (Chudasama et al, 2003; Gourley et al, 2010; Killcross and Coutureau, 2003; Mar et al, 2011; Peters et al, 2009).”

“This is not surprising given that it is well known that the medial and lateral OFC have distinct neuro-anatomical connections (Ferry et al. 2000; Kondo et al. 2003, 2005) and functional roles (Noonan et al. 2010; Mar et al. 2011; Bechara 2005).”

“The absence of such integrative value comparisons due to VMPFC damage may affect delay-discounting by requiring the adoption of simple choice strategies that may then lead to more or less impulsive decisions depending on the nature of the task (Mar et al., 2011).”

“This phenomenon of ‘impulsive choice’ resembles the behavior sometimes observed following orbitofrontal damage (Mobini et al., 2002; Rudebeck et al., 2006; Mar et al., 2011).”

“The reason for this finding is not clear, but there have been multiple studies reporting different functions between the lateral and medial OFC, especially in reward-associated decision-making [22].”

“The dense labeling within the orbitofrontal and retrosplenial cortices suggest cerebellar impact on functions related to choice-making behavior (Mar et al., 2011) and performance in spatial learning tasks (St-Laurent et al.”

“Larger lesions of the OFC in rats have been reported to either increase (Winstanley et al. 2004; Mar et al. 2011) or decrease (Mobini et al. 2002; Rudebeck et al. 2006) preference for larger, delayed rewards.”

“Indeed, others have shown that mOFC (Stopper et al., 2014) but not lOFC (St Onge and Floresco, 2010) inactivation increases risk-taking in a probability discounting task (Mar et al., 2011).”

“Go/no-go test was performed 20 min after injections.”

“The selective reduction of PV+ cell density and PV mRNA in OFC suggests a role for PV+ interneuron dysfunction in the effects of ELS on rule-reversal learning in females (Bissonette et al., 2008; Lodge, 2011; Mar et al., 2011).”

“Specifically, when OCD patients view neutral faces (Cannistraro et al., 2004; Britton et al., 2010) or are anticipating rewards (Marsh et al., 2015), amygdala is hypoactive compared to controls (but see Simon et al., 2014).”

“Impulsive-like behavior becomes evident in rodents with damage to the lateral orbitofrontal cortex (Mar et al., 2011; Bidzan et al., 2012; Johnson et al., 2013).”

“472 Research in primates and rats suggest that the OFC can be functionally segregated 473 into medial and lateral subregions (Elliott et al, 2000; Iversen et al, 1970; Kringelbach and 474 Rolls, 2004; Mar et al, 2011).”

“…on functional differences between medial and lateral OFC subregions in both rodents (Balleine et al., 2011; Bradfield et al., 2015; Corwin et al., 1994; Izquierdo, 2017; Mar et al., 2011) and primates (Bouret and Richmond, 2010; Noonan et al., 2010; Rudebeck and Murray, 2011a; Walton et al., 2015).”

“In the case of the OFC the picture is a little more mixed in the preclinical literature, however Mar et al. (2011) showed that lesions of the lateral OFC in rodents induced impulsivity in a delayed discounting paradigm (whereasmedial orbital lesions had the opposite effect).”

“Thus, the extent to which a “location” can be considered an integrated stimulus and thereby offer a suitable experimental setting to test Rolls’ flexible stimulus–reward mapping theory may depend on task design, species, and the subregion of OFC under investigation (Butter et al., 1969; Meunier et al., 1997; Boulougou…”

“2004), delay-discounting with spatial reversal (Mar et al. 2011), and probabilistic spatial reversal learning (Dalton et al.”

“The OFC is generally conceived to be involved in stimulus–reward association (Schoenbaum et al., 1998; Rolls, 2000; Chudasama and Robbins, 2003; Dalley et al., 2004), and evidence does indicate that subdivisions are functionally different (Mar et al., 2011).”

“At first, our finding that OFC inactivation had no effect on intertemporal choice may appear inconsistent with findings of previous studies that rat OFC lesions result in more impulsive choices (Mobini et al., 2002), less impulsive choices (Winstanley et al., 2004), or both (Mar et al., 2011).”

“In a recent study, lesions selective to the lateral and medial OFC made rats more and less impulsive, respectively, whereas whole OFC lesions induced only a transient change that disappeared with extended training (Mar et al., 2011).”

“…role in reward processing and decision making, and adolescents who have thinner cortical thickness of the para orbitalis and OFC regions may have higher impulsivity to short-term reward and poorer ability to inhibit themselves for a delayed reward, which leads to uncontrolled internet use [74,75].”

“The behavioral paradigm was based on the previously published protocols (Mar and Robbins, 2007; Mar et al, 2011).”

“Observed OFC activity patterns vary with task parameters, experimental design features, analytic methods, and species (Boulougouris et al., 2007; Butter et al., 1969; Kennerley and Wallis, 2009; Mar et al., 2011; Meunier et al., 1997; Rich and Wallis, 2016).”

“Indeed, the OFC has been implicated in impulsive behaviour (Chudasama et al., 2003; Eagle et al., 2008; Mar et al., 2011), albeit in different aspects of impulse control than the PrL (for reviews see Eagle and Baunez, 2010; Pattij and Vanderschuren, 2008).”

“The modulation of gamma power by theta phase in this behavioral period may be instrumental in forging links through Hebbian, spiketiming-dependent plasticity (Bi and Poo, 1998; Cassenaer and Laurent, 2007; Canolty and Knight, 2010) between units that are part of assemblies representing stimulus-outcome and actionoutco…”

“Damage to prefrontal regions often diminishes tolerance for delay, biasing behavior toward choices with immediate payoff (Mar et al. 2011; Rudebeck et al. 2006; A. R. Abela :Y. Chudasama (*) Department of Psychology, McGill University, Montreal, QC H3A 1B1, Canada e-mail:…”

“More specifically, subregions of the OFC have been implicated in delay discounting with lesions of the medial OFC increasing delay discounting in rats and lesions of the lateral OFC decreasing delay discounting (Mar et al. 2011).”

“These inconsistent findings may relate to the extent and anatomical specificity of the lesion site across studies (e.g., Mar et al., 2011).”

“This dissociation has become clearer as researchers start to apply focal lesions to different aspects of the OFC in rats and primates (Iversen and Mishkin 1970; Noonan et al. 2010; Rygula et al. 2010; Mar et al. 2011; Rudebeck and Murray 2011a, 2011b).”

“Impulsivity is generally attributed to changes in orbitofrontal and prefrontal cortex function [34,35].”

“Eagle et al , 2008; Mar et al , 2011), lesioned animals were impaired at stopping.”

“Such an opposing behavioral pattern has been seen when comparing selective (and combined) lesions of medial orbital and lateral orbital regions of the OFC in rats on their ability to select between immediate and delayed reward (Mar et al., 2011).”

“OFC lesions decrease and increase discounting functions depending on experimental design and lesion location (Mobini et al., 2002; Winstanley et al., 2004b; Rudebeck et al., 2006; Winstanley, 2007; Churchwell et al., 2009; Sellitto et al., 2010; Zeeb et al., 2010; Mar et al., 2011).”

“…has recently been shown to be important for using information about outcomes to guide behavior when those outcomes are hidden (Bradfield et al., 2015), risky (Stopper and Floresco, 2014), or temporally delayed, although there are conflicting results for this latter finding (Mar et al., 2011).”

“Fighting was defined as follows according to the criteria by Ulrich and Azrin (1962): both rats face each other in an upright position, their heads thrust forward, they open their mouths, and they strike vigorously at each other.”

“Moreover, damage to this region in humans has been linked to impulsive economic decisions (Koenigs et al. 2010; Mar et al. 2011).”

“However, it should be noted that, after extensive re-training, lesions of the mOFC can enhance impulsive choice (Mar et al. 2011).”

“…and Woods (2013) 0–60 2 8 ✓ Kolokotroni et al. (2011) 0–60 2 10 Krebs and Anderson (2012) 0–60 2 6 ✓ ✓ Loos et al. (2010) 0–40 2 10 Lovic et al. (2011) 0–40 2 10 ✓ ✓ Madden et al. (2010) 0–30 4 6 ✓ ✓ Mar et al. (2011) 0–60 2 10 ✓ Mendez et al. (2010) 0–60 2 10 Mendez et al. (2012) 0–32 2 10…”

“In rats, the neural system mediating discounting includes the nucleus accumbens (NAc), basolateral amygdala (BLA), and orbitofrontal cortex (OFC) (Cardinal et al., 2001; Mobini et al., 2002; Winstanley et al., 2004; Rudebeck et al., 2006; Bezzina et al., 2007; Floresco et al., 2008; Kalenscher and Pennartz, 2008; Chur…”

“However, there is a need for caution in interpreting the results of this study (Mar et al. 2011) in conjunction with the former study (Rudebeck et al. 2006) since they used different decision making tasks and brought about opposing results when the entire OFC region was lesioned.”

“Rodents with lesions to the mOFC and NAcc and human patients with vmPFC/OFC lesions discount monetary and food rewards more steeply (Cardinal et al. 2001; Sellitto et al. 2010; Mar et al. 2011).”

“Likewise, previous research suggests that the neural systems that contribute to the processes of subjective value and DD are divergent (Bezzina et al. 2008; Mar et al. 2011).”

“In rat, functional heterogeneity of the OFC has also been reported [20,76,77].”

“For instance, lesions in the lateral and medial portions of the OFC in rats increase or decrease, respectively, impulsivity (Mar et al. 2011).”

“ORIGINAL RESEARCH ARTICLE published: 08 May 2014 doi: 10.3389/fnins.2014.00104 Proactive and reactive inhibitory control in rats”

“The performance of the rats was analyzed according to the assumptions of the race model, which assumes that go and stop processes are independent from each other (Logan and Cowan 1984).”

“Medial PFC, [14,15] No difference # Orbitofrontal cortex — whole, [16–19] #/No difference # Orbitofrontal cortex — medial [17] " Orbitofrontal cortex — lateral [17] # Infralimbic cortex [16,20,21] No difference # Anterior cingulate [22,20] No difference Medial Striatum [23 ] " NAC core, [22,24,14] " No difference Subt…”

“For instance, when using the delay discounting task (Mar et al. 2011; Stanis et al. 2008) upon completion of the entire session, a rat’s energy intake can be as high as ∼36 kcal.”

“These discrepancies may result from differential destruction of subregions of OFC, as lesions to medial OFC increase sensitivity to delayed reinforcement, whereas lesions to lateral OFC decrease impulsive choice (Mar et al., 2011).”

“Such brain regions include the nucleus accumbens, basolateral amygdala, hippocampus, and orbitofrontal cortex (OFC), which are also recognized for controlling impulsive decision making (Cardinal et al. 2001; Winstanley et al. 2004; Cheung and Cardinal 2005; Churchwell et al. 2009; Galtress and Kirkpatrick 2010; Zeeb e…”