Vedran Lovic

Mothering begets mothering: The transmission of behavior and its neurobiology across generations

Early experiences exert their effects on adult parental behavior in part by altering the development of neurobiological mechanisms that initiate or support the initiation and sustenance of adult parental behavior. The effects of parental behavior on sensory, perceptual and emotional mechanisms in offspring constitute an experientially based mechanism by which neurobiological factors regulating behavior can be transferred from generation to generation somewhat independently of genetic endowment.

Quantifying Individual Variation in the Propensity to Attribute Incentive Salience to Reward Cues

If reward-associated cues acquire the properties of incentive stimuli they can come to powerfully control behavior, and potentially promote maladaptive behavior. Pavlovian incentive stimuli are defined as stimuli that have three fundamental properties: they are attractive, they are themselves desired, and they can spur instrumental actions. We have found, however, that there is considerable individual variation in the extent to which animals attribute Pavlovian incentive motivational properties (“incentive salience”) to reward cues. The purpose of this paper was to develop criteria for identifying and classifying individuals based on their propensity to attribute incentive salience to reward cues. To do this, we conducted a meta-analysis of a large sample of rats (N = 1,878) subjected to a classic Pavlovian conditioning procedure. We then used the propensity of animals to approach a cue predictive of reward (one index of the extent to which the cue was attributed with incentive salience), to characterize two behavioral phenotypes in this population: animals that approached the cue (“sign-trackers”) vs. others that approached the location of reward delivery (“goal-trackers”). This variation in Pavlovian approach behavior predicted other behavioral indices of the propensity to attribute incentive salience to reward cues. Thus, the procedures reported here should be useful for making comparisons across studies and for assessing individual variation in incentive salience attribution in small samples of the population, or even for classifying single animals.

Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex

RationaleRepeated exposure to psychomotor stimulants can lead to sensitization to their effects, and sensitization has been implicated in the pathophysiology of schizophrenia and drug abuse. These disorders are characterized by cognitive deficits, particularly in prefrontally mediated executive function.ObjectiveThe present experiments were conducted to investigate the effects of sensitizing regimens of amphetamine and phencyclidine (PCP) on attentional set shifting.MethodsRats received injections of amphetamine, PCP or saline three times per week for 5 weeks. Four weeks later, rats were trained to dig for food in one of two bowls, each bowl having an odour and a texture. Only one dimension (odour or texture) correctly predicted which bowl was baited. Rats were then tested on a series of discriminations including those requiring an intra-dimensional shift (IDS), an extra-dimensional shift (EDS) or a reversal of previously relevant and irrelevant stimuli.ResultsRats sensitized to amphetamine performed normally on the IDS, but were impaired on the EDS, as well as on reversal discriminations. PCP-sensitized rats were unaffected on any of the discriminations. In amphetamine-sensitized rats the deficit at the EDS stage was reversed by infusion of the D1 receptor agonist SKF38393 into the medial prefrontal cortex (mPFC).ConclusionsResults show that the amphetamine-sensitized state impairs prefrontally mediated attentional set shifting. This is consistent with cognitive deficits in schizophrenia and addiction, and with the evidence that amphetamine sensitization is accompanied by functional changes in the mPFC. These results further add to a growing literature showing that activating D1 receptors in the mPFC improves aspects of cognition.

Medial Prefrontal Cortex Lesions in the Female Rat Affect Sexual and Maternal Behavior and Their Sequential Organization

Temporal sequences of sexual and maternal behaviors in female rats and their correlation with each other and with performance on a sensory-motor gating response inhibition task assessed by prepulse inhibition (PPI) were investigated following medial prefrontal cortex (mPFC) lesions. Following excitotoxic mPFC (n = 10) or sham (n = 9) lesions, sexual behaviors across the ovarian cycle were scored. After mating and parturition, maternal interactions were scored until pups reached postnatal Day 10. After resumption of the ovarian cycle, the female rats were tested for PPI. Compared with sham lesions, mPFC lesions impaired proceptive behaviors and some maternal behaviors (e.g., pup retrieval, pup licking) but did not affect others (e.g., nest building, pup mouthing). Lesions disrupted temporal sequences of solicitations (number of male orientations followed, within 4 s, by a level change) and pup retrievals (number of pup retrievals followed, within 5 s, by another retrieval). These sequential behavior patterns were significantly correlated with each other and with PPI. However, when PPI effects were partialled out, group differences were less strong, but persisted. This study demonstrated that mPFC manipulations affect actions rich in sequential structure in response to biologically relevant stimuli.

Early Adversity Alters Attention and Locomotion in Adult Sprague-Dawley Rats

This study investigated the effects of prenatal stress and its interaction with artificial rearing (AR) on adult rat behavior. Pregnant dams underwent restraint stress from Gestational Day 10 to 21. After parturition, pups were raised by their mothers or in the AR paradigm, with or without stroking stimulation. In adulthood, rats were tested on prepulse inhibition (PPI), locomotor activity, elevated plus-maze, and spatial working memory. There were main effects and interactions of both prenatal stress and AR on activity. Additional stimulation reduced activity in nonstressed AR rats but increased activity in prenatally stressed AR rats. AR altered PPI and plus-maze behavior whereas additional stimulation partially reversed these effects. This study demonstrates that prenatal experiences can modulate the effects of postnatal treatments.

Variation in the form of Pavlovian conditioned approach behavior among outbred male Sprague-Dawley rats from different vendors and colonies: sign-tracking vs. goal-tracking.

Even when trained under exactly the same conditions outbred male Sprague-Dawley (SD) rats vary in the form of the Pavlovian conditioned approach response (CR) they acquire. The form of the CR (i.e. sign-tracking vs. goal-tracking) predicts to what degree individuals attribute incentive salience to cues associated with food or drugs. However, we have noticed variation in the incidence of these two phenotypes in rats obtained from different vendors. In this study, we quantified sign- and goal-tracking behavior in a reasonably large sample of SD rats obtained from two vendors (Harlan or Charles River), as well as from individual colonies operated by both vendors. Our sample of rats acquired from Harlan had, on average, more sign-trackers than goal-trackers, and vice versa for our sample of rats acquired from Charles River. Furthermore, there were significant differences among colonies of the same vendor. Although it is impossible to rule out environmental variables, SD rats at different vendors and barriers may have reduced phenotypic heterogeneity as a result of genetic variables, such as random genetic drift or population bottlenecks. Consistent with this hypothesis, we identified marked population structure among colonies from Harlan. Therefore, despite sharing the same name, investigators should be aware that important genetic and phenotypic differences exist among SD rats from different vendors or even from different colonies of the same vendor. If used judiciously this can be an asset to experimental design, but it can also be a pitfall for those unaware of the issue.

Early-life maternal separation and social isolation produce an increase in impulsive action but not impulsive choice.

Early life environment, events, and context, such as mother-offspring relationship, can have profound effects on future behavior and physiology. We investigated the effects of long-term maternal and social separation, through artificial rearing, on adult impulsivity. Rats were maternally reared (MR) or artificially reared (AR) and half of the AR rats were provided with replacement somatosensory stimulation intended to simulate maternal licking. There are at least 2 forms of impulsivity and we compared rats on 1 test of impulsive action (differential reinforcement of low rates of responding-DRL-20s) and 2 tests of impulsive choice (delay discounting and fixed consecutive number schedule-FCN). We found that AR rats are more action impulsive; however, this effect can be reduced by maternal licking-like stimulation. In contrast, AR rats did not display an increase in impulsive choice. Overall, these experiments show that early life maternal and social separation have different effects on the 2 forms of impulsivity.

Rapid dopamine transmission within the nucleus accumbens: Dramatic difference between morphine and oxycodone delivery

While most drugs of abuse increase dopamine neurotransmission, rapid neurochemical measurements show that different drugs evoke distinct dopamine release patterns within the nucleus accumbens. Rapid changes in dopamine concentration following psychostimulant administration have been well studied; however, such changes have never been examined following opioid delivery. Here, we provide novel measures of rapid dopamine release following intravenous infusion of two opioids, morphine and oxycodone, in drug‐naïve rats using fast‐scan cyclic voltammetry and rapid (1 min) microdialysis coupled with high‐performance liquid chromatography ‐ tandem mass spectrometry (HPLC‐MS). In addition to measuring rapid dopamine transmission, microdialysis HPLC‐MS measures changes in GABA, glutamate, monoamines, monoamine metabolites and several other neurotransmitters. Although both opioids increased dopamine release in the nucleus accumbens, their patterns of drug‐evoked dopamine transmission differed dramatically. Oxycodone evoked a robust and stable increase in dopamine concentration and a robust increase in the frequency and amplitude of phasic dopamine release events. Conversely, morphine evoked a brief (~ 1 min) increase in dopamine that was coincident with a surge in GABA concentration and then both transmitters returned to baseline levels. Thus, by providing rapid measures of neurotransmission, this study reveals previously unknown differences in opioid‐induced neurotransmitter signaling. Investigating these differences may be essential for understanding how these two drugs of abuse could differentially usurp motivational circuitry and powerfully influence behavior.

Individual Variation in Incentive Salience Attribution and Accumbens Dopamine Transporter Expression and Function

Cues (conditioned stimuli; CSs) associated with rewards can come to motivate behavior, but there is considerable individual variation in their ability to do so. For example, a lever‐CS that predicts food reward becomes attractive and wanted, and elicits reward‐seeking behavior, to a greater extent in some rats (‘sign‐trackers’; STs) than others (‘goal‐trackers’; GTs). Variation in dopamine (DA) neurotransmission in the nucleus accumbens (NAc) core is thought to contribute to such individual variation. Given that the DA transporter (DAT) exerts powerful regulation over DA signaling, we characterized the expression and function of the DAT in the accumbens of STs and GTs. STs showed greater DAT surface expression in ventral striatal synaptosomes than GTs, and ex vivo fast‐scan cyclic voltammetry recordings of electrically evoked DA release confirmed enhanced DAT function in STs, as indicated by faster DA uptake, specifically in the NAc core. Consistent with this, systemic amphetamine (AMPH) produced greater inhibition of DA uptake in STs than in GTs. Furthermore, injection of AMPH directly into the NAc core enhanced lever‐directed approach in STs, presumably by amplifying the incentive value of the CS, but had no effect on goal‐tracking behavior. On the other hand, there were no differences between STs and GTs in electrically‐evoked DA release in slices, or in total ventral striatal DA content. We conclude that greater DAT surface expression may facilitate the attribution of incentive salience to discrete reward cues. Investigating this variability in animal sub‐populations may help explain why some people abuse drugs while others do not.

Early postnatal experience and DRD2 genotype affect dopamine receptor expression in the rat ventral striatum.

Dopamine systems can be altered by experiences such as early life adversity. The intensity of these effects seems to vary as a function of interactions between genetic and environmental influences. In a series of experiments we have investigated the effects of genetic variants and early life adversity on several biobehavioral outcomes. Here we investigated the presence of single nucleotide polymorphisms (SNPs) in the gene coding for dopamine D2 receptors (DRD2) and the interaction between these variants with early life adversity on the expression of D2 receptors in the striatum. Time-mated pregnant female rats underwent restraint stress (gestational days 10-21) or were left undisturbed. Following parturition rat pups were maternally reared (MR) or artificially reared (AR). Subsequent to adult behavioral testing, rats were genotyped and their brains were processed (autoradiography) for D2 receptor expression. We found three variants in the DRD2 gene and these variants interacted with early adversity to affect D2 receptor expression in the nucleus accumbens. Specifically, artificially reared rats with AG DRD2 variant showed significantly higher D2 expression compared to mother reared rats with the AG DRD2 variant as well as the artificially reared rats with a GG DRD2 variant. These findings show that adult D2 expression is significantly influenced by the interaction of DRD2 SNPs and early developmental factors. These finding may explain why there are significant individual differences in the impact of early life adversity on dopamine-dependent processes and disorder vulnerabilities.