Mariana Pereira

Functional mapping of the neural circuitry of rat maternal motivation: effects of site-specific transient neural inactivation

The present review focuses on recent studies from our laboratory examining the neural circuitry subserving rat maternal motivation across postpartum. We employed a site‐specific neural inactivation method by infusion of bupivacaine to map the maternal motivation circuitry using two complementary behavioural approaches: unconditioned maternal responsiveness and choice of pup‐ over cocaine‐conditioned incentives in a concurrent pup/cocaine choice conditioned place preference task. Our findings revealed that, during the early postpartum period, distinct brain structures, including the medial preoptic area, ventral tegmental area and medial prefrontal cortex infralimbic and anterior cingulate subregions, contribute a pup‐specific bias to the motivational circuitry. As the postpartum period progresses and the pups grow older, it is further revealed that maternal responsiveness becomes progressively less dependent on the medial preoptic area and medial prefrontal cortex infralimbic activity, and more distributed in the maternal circuitry, such that additional network components, including the medial prefrontal cortex prelimbic subregion, are recruited with maternal experience, and contribute to the expression of late postpartum maternal behaviour. Collectively, our findings provide strong evidence that the remarkable ability of postpartum females to successfully care for their developing infants is subserved by a distributed neural network that carries out efficient and dynamic processing of complex, constantly changing incoming environmental and pup‐related stimuli, ultimately allowing the progression of appropriate expression and waning of maternal responsiveness across the postpartum period.

Role of maternal behavior on aggression, fear and anxiety.

Concomitant to the expression of maternal behavior, the lactating female develops anxiolysis in the elevated plus maze test, aggression towards intruders and reduced fear in response to a sudden auditory stimulus. This study aims to determine if these behavioral changes are associated with maternal behavior independently of the endocrine status that characterizes gestation, parturition and lactation. To assess this purpose, the behavior of lactating females was compared to that exhibited by maternal and nonmaternal ovariectomized rats untreated with steroid hormones. In contrast with lactating dams, sensitized animals (rats that displayed maternal behavior after a continuous contact with young pups) did not display reduced anxiety in the plus maze test. However, the sensitized females showed behaviors characteristic of lactating rats, such as some components of maternal aggression and reduced fear, though much less intensely than dams. These results suggest that aggression and reduced fear, but not anxiolysis, partially depend on the development of maternal behavior.

Experimental anxiety in the black and white model in cycling, pregnant and lactating rats

This study demonstrates changes in experimental anxiety assessed in the black and white paradigm during various reproductive states of female rats. Low levels of experimental anxiety were observed during late proestrus and on day 17 of gestation, stages related to high progesterone (P) levels. In estrus, metestrus, diestrus and on day 21 of gestation, stages characterized by low P concentrations, high levels of experimental anxiety, similar to those exhibited by ovariectomized females, were found. No changes in experimental anxiety were observed on day 8 of lactation compared to ovariectomized females. These data are discussed from the standpoint of the putative anxiolytic-like effect of progestins.

Demanding pups improve maternal behavioral impairments in sensitized and haloperidol-treated lactating female rats

The impairments in the maternal behavior of ovariectomized sensitized females, relative to lactating dams, resemble those deficits found in lactating females after treatment with the D1/D2 DA receptor antagonist haloperidol, which interferes with maternal motivation. Therefore, it could be speculated that these behavioral deficits found in sensitized females and haloperidol-treated dams are due to a reduced motivation to interact with pups. In support of this hypothesis, we have found that both sensitized and haloperidol-treated lactating females exhibited remarkably similar impairments in the expression of all active maternal behaviors relative to lactating dams. Furthermore, these deficits were overridden when they were allowed to interact with 12h-isolated pups (demanding pups). Interestingly, lactating dams also improved their maternal behavior in the presence of demanding pups, and clearly chose demanding more than non-demanding pups in a preference paradigm. These data support the idea that the behavioral deficits of sensitized and haloperidol-treated lactating females are due to a reduced behavioral activation in response to the incentive cues from pups compared to lactating dams, and not because of a motor inability to express maternal behavior. These findings ultimately suggest that pups modulate the activity of DA system involved in the regulation of maternal behavior.

Flexibility and adaptation of the neural substrate that supports maternal behavior in mammals

Maternal behavior is species-specific and expressed under different physiological conditions, and contexts. It is the result of neural processes that support different forms (e.g. postpartum, cycling sensitized and spontaneous maternal behavior) and modalities of mother-offspring interaction (e.g. maternal interaction with altricial/precocious young; selective/non-selective bond). To understand how the brain adapts to and regulates maternal behavior in different species, and physiological and social conditions we propose new neural models to explain different forms of maternal expression (e.g. sensitized and spontaneous maternal behavior) and the behavioral changes that occur across the postpartum period. We emphasize the changing role of the medial preoptic area in the neural circuitry that supports maternal behavior and the cortical regulation and adjustment of ongoing behavioral performance. Finally, we discuss how our accumulated knowledge about the psychobiology of mothering in animal models supports the validity of animal studies to guide our understanding of human mothering and to improve human welfare and health.

The changing role of the medial preoptic area in the regulation of maternal behavior across the postpartum period: facilitation followed by inhibition

Maternal behavior in rats undergoes considerable plasticity in parallel to the developmental stage of the pups, resulting in distinct patterns of maternal behavior and care at different postpartum time points. The medial preoptic area (mPOA) of the hypothalamus is one critical neural substrate underlying the onset and early expression of maternal behavior in rats but little is known about its specific functional role in the evolving expression of maternal behavior across the postpartum period. The present study uses a reversible local neural inactivation method to examine the role of the mPOA in the regulation of maternal behavior throughout the postpartum period, particularly extending into the late postpartum, a little examined period. This approach avoids the compensatory plasticity in CNS that occurs after permanent lesions, and allows the repeated testing of same individuals. Early (PPD7-8) and late (PPD13-14) postpartum maternal behavior was evaluated in female rats following infusions of bupivacaine or vehicle into the mPOA or into control areas. As expected, mPOA inactivation severely but transiently disrupted early postpartum maternal behavior whereas infusion of vehicle or inactivation of adjacent control sites did not. Later in the postpartum period, however, transient mPOA inactivation facilitated the expression of maternal behaviors, highly contrasting the behavioral expression levels characteristic of late postpartum. Results strongly demonstrate that the mPOA is differentially engaged throughout postpartum in orchestrating appropriate maternal responses with the developmental stage of the pups.

New theoretical and experimental approaches on maternal motivation in mammals.

Maternal behavior is expressed in different modalities, physiological conditions, and contexts. It is the result of a highly motivated brain, that allows the female to flexibily adapt her caring activities to different situations and social demands. To understand how mothers coordinate maternal and other motivated behaviors we discuss the limitations of current theoretical approaches to study maternal motivation (e.g. distinction between appetitive and consummatory behaviors), and propose a different approach (i.e. motorically active vs. passive motivations) and a distinction between maternal motivated state and maternal motivated behaviors. We review the evidence supporting dopamine mediation of maternal motivation and describe how different phases of the dopaminergic response - basal, tonic, and phasic release in the nucleus accumbens - relate to increased salience, invigorating behavior, and behavioral switching. The existing and new experimental paradigms to investigate maternal motivation, and its coexpression and coordination with other social or non-social motivations are also analyzed. An example of how specificity of motivational systems (e.g. maternal and sexual behavior at postpartum estrus) could be processed at the neural level is also provided. This revision offers new theoretical and experimental approaches to address the fundamental question of how mothers flexibly adapt and coordinate the different components of maternal behavior with other motivated behaviors, also critical for the survival of the species.

Characterization of maternal motivation in the lactating rat: Contrasts between early and late postpartum responses

We previously assessed the motivational properties of pups relative to those of cocaine in parturient female rats (dams) across the postpartum period and demonstrated that the larger subset of dams in early postpartum (PPD8) preferred the pup-associated chamber, whereas the majority of dams tested in late postpartum (PPD16) preferred the cocaine-associated chamber [Mattson, B.J., Williams, S., Rosenblatt, J.S., Morrell, J.I. 2001. Comparison of two positive reinforcing stimuli: pups and cocaine throughout the postpartum period. Behav. Neurosci., 115, 683-694; Seip, K.M., Morrell, J.I. 2007. Increasing the incentive salience of cocaine challenges preference for pup- over cocaine-associated stimuli during early postpartum: place preference and locomotor analyses in the lactating female rat. Psychopharmacology 194, 309-319]. The present study uses a dual-choice conditioned place preference to ask how the progression of the postpartum period, including natural pup development, influences maternal motivation for pups. Preferences for cued chambers associated with pups that were age-matched to the postpartum stage of the dam in contrast to a stimulus with little incentive salience were higher during the early than the late postpartum, suggesting that the incentive salience of pups diminishes as the postpartum period progresses. Preferences of the early postpartum dams deprived of pups for 15 min, 2, 6, 12 or 22 hrs prior to conditioning and testing did not differ statistically but there was a trend of more pup preference after 22 hr deprivation; pup age was not an important factor in early postpartum. In marked contrast, late postpartum dams only exhibited robust pup-associated place preference when they were conditioned with young (4-7 day-old) pups or after a 22 hr period of deprivation from contemporaneous pups. Together these results suggest that both forces are at work in the mother-pup dyad, changes in the pups as they develop and changes in the physiological and endocrine state of the female as she progresses through the postpartum period.

The medial preoptic area is necessary for motivated choice of pup- over cocaine-associated environments by early postpartum rats.

Converging evidence suggests that the motivation to seek cocaine during the postpartum period is significantly impacted by the competing incentives of offspring, a stimulus unique to this life stage. In the present study, the functional role of the medial preoptic area (mPOA), a critical site involved in maternal responsiveness, on processing incentive value of pup-associated cues and influencing response allocation for pup- over cocaine-associated environments was investigated using a concurrent pup/cocaine choice conditioned place preference (CPP) paradigm. Early postpartum females with bilateral guide cannulae aimed into the mPOA or into anatomical control sites were conditioned, from postpartum days (PPD) 4 to 7, to associate different uniquely featured environments with pups or cocaine. CPP was tested on PPD8 following intra-mPOA infusions of either 2% bupivacaine or saline vehicle. In two additional experiments, the effects of intra-mPOA infusions of bupivacaine on expression of conditioned responding induced by environments associated with either pups or cocaine were examined separately. Transient inactivation of the mPOA selectively blocked the conditioned preferences for pup-associated environments, significantly contrasting the robust pup-CPP found in non-surgical and intra-mPOA vehicle-treated females. In contrast, mPOA inactivation failed to alter cocaine-CPP in postpartum females. When given a choice between environments associated with pups or cocaine, transient functional inactivation of the mPOA altered choice behavior, biasing the preference of females toward cocaine-associated environments, such that almost all preferred cocaine- and none the pup-associated option. The anatomical specificity was revealed when inactivation of adjacent regions to the mPOA did not affect CPP responses for pups. The findings support a critical role for the mPOA in mediating pup-seeking behavior, and further suggest that the competing properties of pups over alternative incentives, including drugs of abuse, rely on mPOA integrity to provide relevant pup-related information to the circuitry underlying the choice behavior between pups and alternative stimuli.

Incentive salience of cocaine across the postpartum period of the female rat.

Rationale–ObjectivesOur prior conditioned place preference (CPP) work demonstrates that late (day16) postpartum female rats consistently prefer cocaine- over pup-associated chambers, whereas far fewer early postpartum (day8) females prefer the cocaine-associated chamber. The present study examines early and late postpartum females’ preference for a cocaine-associated chamber when contrasted with a chamber associated with saline (rather than pups).Materials and methodsPostpartum females were tested for conditioned preference for chambers associated with cocaine (10 mg/kg subcutaneous (SC) or 0.5, 5, 10, or 20 mg/kg intraperitoneal (IP) injections) versus saline; preferences of virgin female and male rats for select cocaine stimuli (10mg/kg SC or IP) were also tested. Locomotion was recorded during CPP conditioning and testing.ResultsEarly and late postpartum females expressed strikingly similar preference for the cocaine-associated chamber across all administration routes and doses. IP cocaine produced an orderly, inverted U-shaped dose-preference curve, with preference peaking at the 5 mg/kg dose (83% of females). While many postpartum females preferred 10mg/kg cocaine administered either SC or IP, both virgin females and males expressed strong aversion to SC cocaine and, while virgin females strongly preferred IP cocaine, males remained relatively indifferent. Across 10mg/kg IP cocaine-conditioning sessions, locomotor sensitization occurred exclusively in cocaine- but not saline-preferring postpartum females. Locomotor rate was lower in preferred versus nonpreferred chambers at CPP test.ConclusionsEarly and late postpartum females may be equally and uniquely susceptible to sampling and/or abuse of modestly salient doses of cocaine (10mg/kg SC; 5mg/kg IP) compared to virgin females and/or males.