Raising overlapping litters: Differential activation of rat maternal neural circuitry after interacting with newborn or juvenile pups

The maternal behaviour of a rat dynamically changes during the postpartum period, adjusting to the characteristics and physiological needs of the pups. This adaptation has been attributed to functional modifications in the maternal circuitry. Maternal behaviour can also flexibly adapt according to different litter compositions. Thus, mothers with two overlapping litters can concurrently take care of neonate and juvenile pups, mostly directing their attention to the newborns. We hypothesised that the maternal circuitry of these mothers would show a differential activation pattern after interacting with pups depending on the developmental stage of their offspring. Thus, we evaluated the activation of several areas of the maternal circuitry in mothers of overlapping litters, using c‐Fos immunoreactivity as a marker of neuronal activation, after interacting with newborns or juveniles. The results showed that mothers with overlapping litters display different behavioural responses towards their newborn and their juvenile pups. Interestingly, these behavioural displays co‐occurred with specific patterns of activation of the maternal neural circuitry. Thus, a similar expression of c‐Fos was observed in some key brain areas of mothers that interacted with newborns or juveniles, such as the medial preoptic area and the nucleus accumbens, whereas a differential activation was quantified in the ventral region of the bed nucleus of the stria terminalis, the infralimbic and prelimbic subregions of the medial prefrontal cortex and the basolateral and medial nuclei of the amygdala. We posit that the specific profile of activation of the neural circuitry controlling maternal behaviour in mothers with overlapping litters enables dams to respond adequately to the newborn and the juvenile pups.     

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.     

Fos expression following self-stimulation of the medial prefrontal cortex

Self-stimulation of the medial prefrontal cortex and medial forebrain bundle appears to be mediated by different directly activated fibers. However, reward signals from the medial prefrontal cortex do summate with signals from the medial forebrain bundle, suggesting some overlap in the underlying neural circuitry. We have previously used Fos immunohistochemistry to visualize neurons activated by rewarding stimulation of the medial forebrain bundle. In this study, we assessed Fos immunolabeling after self-stimulation of the medial prefrontal cortex. Among the structures showing a greater density of labeled neurons in the stimulated hemisphere were the prelimbic and cingulate cortex, nucleus accumbens, lateral preoptic area, substantia innominata, lateral hypothalamus, anterior ventral tegmental area, and pontine nuclei. Surprisingly, little or no labeling was seen in the mediodorsal thalamic nucleus or the locus coeruleus. Double immunohistochemistry for tyrosine hydroxylase and Fos showed that within the ventral tegmental area, a substantial proportion of dopaminergic neurons did not express Fos. Despite previous suggestions to the contrary, comparison of the present findings with those of our previous Fos studies reveals a number of structures activated by rewarding stimulation of both the medial prefrontal cortex and the medial forebrain bundle. Some subset of activated cells in the common regions showing Fos-like immunoreactivity may contribute to the rewarding effect produced by stimulating either site.     

Neural basis of maternal behavior in the rat

This article presents a review of the neural and neurochemical regulation of maternal behavior in the rat, emphasizing the role of the medial preoptic area (MPOA) and its neural connections in this regulation. Evidence for the role of the MPOA includes the following and will be discussed: (1) Axon-sparing lesions of the MPOA disrupt maternal behavior, indicating the involvement of MPOA neurons rather than fibers of passage. (2) Estradiol acts on the MPOA to facilitate maternal behavior. (3) An MPOA-to-lateral preoptic area-to-ventral tegmental area circuit may be part of the output pathway by which the MPOA influences maternal behavior. (4) MPOA neural circuitry may interact with olfactory neural circuitry and with the motor system to influence maternal responsiveness. (5) Opioid neural pathways appear to inhibit, and oxytocinergic neural pathways appear to promote, maternal behavior.     

Congenital prosopagnosia: multistage anatomical and functional deficits in face processing circuitry

Face recognition is a primary social skill which depends on a distributed neural network. A pronounced face recognition deficit in the absence of any lesion is seen in congenital prosopagnosia. This study investigating 24 congenital prosopagnosic subjects and 25 control subjects aims at elucidating its neural basis with fMRI and voxel-based morphometry. We found a comprehensive behavioral pattern, an impairment in visual recognition for faces and buildings that spared long-term memory for faces with negative valence. Anatomical analysis revealed diminished gray matter density in the bilateral lingual gyrus, the right middle temporal gyrus, and the dorsolateral prefrontal cortex. In most of these areas, gray matter density correlated with memory success. Decreased functional activation was found in the left fusiform gyrus, a crucial area for face processing, and in the dorsolateral prefrontal cortex, whereas activation of the medial prefrontal cortex was enhanced. Hence, our data lend strength to the hypothesis that congenital prosopagnosia is explained by network dysfunction and suggest that anatomic curtailing of visual processing in the lingual gyrus plays a substantial role. The dysfunctional circuitry further encompasses the fusiform gyrus and the dorsolateral prefrontal cortex, which may contribute to their difficulties in long-term memory for complex visual information. Despite their deficits in face identity recognition, processing of emotion related information is preserved and possibly mediated by the medial prefrontal cortex. Congenital prosopagnosia may, therefore, be a blueprint of differential curtailing in networks of visual cognition.     

Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates

The prefrontal cortex has been implicated in a variety of cognitive and executive processes, including working memory, decision-making, inhibitory response control, attentional set-shifting and the temporal integration of voluntary behaviour. This article reviews current progress in our understanding of the rodent prefrontal cortex, especially evidence for functional divergence of the anatomically distinct sub-regions of the rat prefrontal cortex. Recent findings suggest clear distinctions between the dorsal (precentral and anterior cingulate) and ventral (prelimbic, infralimbic and medial orbital) sub-divisions of the medial prefrontal cortex, and between the orbitofrontal cortex (ventral orbital, ventrolateral orbital, dorsal and ventral agranular cortices) and the adjacent medial wall of the prefrontal cortex. The dorso-medial prefrontal cortex is implicated in memory for motor responses, including response selection, and the temporal processing of information. Ventral regions of the medial prefrontal cortex are implicated in interrelated 'supervisory' attentional functions, including attention to stimulus features and task contingencies (or action-outcome rules), attentional set-shifting, and behavioural flexibility. The orbitofrontal cortex is implicated in lower-order discriminations, including reversal of stimulus-reward associations (reversal learning), and choice involving delayed reinforcement. It is anticipated that a greater understanding of the prefrontal cortex will come from using tasks that load specific cognitive and executive processes, in parallel with discovering new ways of manipulating the different sub-regions and neuromodulatory systems of the prefrontal cortex.     

Dendritic morphology in the striatum and hypothalamus differentially exhibits experience-dependent changes in response to maternal care and early social isolation

Changes in neuron morphology, stemming from experiences in early life or adulthood, may be the basis for changes in behavior and their underlying functional mechanisms. For example, reproductive experience has been shown to significantly alter neuron morphology in the hippocampus and prefrontal cortex. In contrast to the effects of reproductive experience, a form of enrichment, on neuron morphology, our understanding of the effects of early social isolation on adult neuron morphology is limited. Therefore, the present study examined changes in neuron morphology in the dorsal (caudate nucleus) and ventral (nucleus accumbens, shell region) striatum and the medial preoptic area of adult virgin and postpartum females exposed to either artificial or maternal rearing during development. Primary results show that regardless of early social isolation, neurons in the caudate nucleus of postpartum females have decreased dendritic complexity compared to virgin females. Maternal experience also increased dendritic complexity in neurons of the nucleus accumbens shell. However, both early social isolation and maternal experience in adulthood influenced dendritic complexity in the medial preoptic area. Together these findings suggest that hypothalamic and striatal neurons show experience-dependent dendritic plasticity and the type and timing of these experiences differentially affect the location and degree of these morphological changes.     

The neural substrate of orientation working memory

We have used positron emission tomography (PET) to identify the neural substrate of two major cognitive components of working memory (WM), maintenance and manipulation of a single elementary visual attribute, i.e., the orientation of a grating presented in central vision. This approach allowed us to equate difficulty across tasks and prevented subjects from using verbal strategies or vestibular cues. Maintenance of orientations involved a distributed fronto-parietal network, that is, left and right lateral superior frontal sulcus (SFSl), bilateral ventrolateral prefrontal cortex (VLPFC), bilateral precuneus, and right superior parietal lobe (SPL). A more medial superior frontal sulcus region (SFSm) was identified as being instrumental in the manipulative operation of updating orientations retained in the WM. Functional connectivity analysis revealed that orientation WM relies on a coordinated interaction between frontal and parietal regions. In general, the current findings confirm the distinction between maintenance and manipulative processes, highlight the functional heterogeneity in the prefrontal cortex (PFC), and suggest a more dynamic view of WM as a process requiring the coordinated interaction of anatomically distinct brain areas.     

Diurnal rhythms in neural activation in the mesolimbic reward system: critical role of the medial prefrontal cortex

Previous evidence suggests a circadian modulation of drug‐seeking behavior and responsiveness to drugs of abuse. To identify potential mechanisms for rhythmicity in reward, a marker of neural activation (cFos) was examined across the day in the mesolimbic reward system. Rats were perfused at six times during the day [zeitgeber times (ZTs): 2, 6, 10, 14, 18, and 22], and brains were analysed for cFos and tyrosine hydroxylase (TH)‐immunoreactive (IR) cells. Rhythmic expression of cFos was observed in the nucleus accumbens (NAc) core and shell, in the medial prefrontal cortex (mPFC), and in TH‐IR and non‐TH‐IR cells in the ventral tegmental area (VTA), with peak expression during the late night and nadirs during the late day. No significant rhythmicity was observed in the basolateral amgydala or the dentate gyrus. As the mPFC provides excitatory input to both the NAc and VTA, this region was hypothesised to be a key mediator of rhythmic neural activation in the mesolimbic system. Hence, the effects of excitotoxic mPFC lesions on diurnal rhythms in cFos immunoreactivity at previously observed peak (ZT18) and nadir (ZT10) times were examined in the NAc and VTA. mPFC lesions encompassing the prelimbic and infralimbic subregions attenuated peak cFos immunoreactivity in the NAc, eliminating the diurnal rhythm, but had no effect on VTA rhythms. These results suggest that rhythmic neural activation in the mesolimbic system may contribute to diurnal rhythms in reward‐related behaviors, and indicate that the mPFC plays a critical role in mediating rhythmic neural activation in the NAc.     

The content of dopamine, serotonin, and their metabolites in the neural circuit that mediates maternal behavior in juvenile and adult rats

Continuous exposure of non-parturient rats to pups can induce maternal behavior similar in most aspects to that found in the postpartum rat. Surprisingly, young juvenile rats (20-24 days of age) only require 1-3 days of exposure to pups, while adults require 4-8 days before maternal behavior emerges. Dopamine (DA) and possibly serotonin (5-HT) may mediate the expression of adult maternal behavior. We hypothesize that postnatal changes in DA and 5-HT within the neural circuit that supports maternal behavior including the medial preoptic area (MPOA), medial and cortical amygdala (MCA), and nucleus accumbens (NAC), may underlie these differences in responsiveness across juveniles and adults. We measured DA, 5-HT, and their metabolites in postmortem samples of these regions in maternal and non-maternal juvenile and adult females. The only difference found across behavioral groups was that the MPOA of adults induced into maternal behavior by pup exposure had more DA than did that of isolated adult females or maternal juveniles. However, when adults versus juveniles were compared, the content of DA and 3,4-dihydroxyphenylacetic (DOPAC) was higher in the adult than in the juvenile NAC and MCA; the content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in these structures did not vary across the age groups. In contrast, higher levels of 5-HT and 5-HIAA were found in the MPOA in juveniles compared to adults. We propose that these region-specific age differences in DA and 5HT may underlie differences in juvenile-adult responses to pups.     

Taking a different perspective: Mindset influences neural regions that represent value and choice

Most choices are complex and can be considered from a number of different perspectives. For example, someone choosing a snack may have taste, health, cost or any number of factors at the forefront of their mind. Although previous research has examined neural systems related to value and choice, very little is known about how mindset influences these systems. In the current study, participants were primed with Health or Taste while they made decisions about snack foods. Some neural regions showed consistent associations with value and choice across Health or Taste mindsets. Regardless of mindset, medial orbitofrontal cortex (MOFC) tracked value in terms of taste, regions in left lateral prefrontal cortex (LPFC) tracked value in terms of health, and MOFC and dorsal anterior cingulate were associated with choice. However, activity in other neural regions was modulated by the mindset manipulation. When primed with Taste, rostral anterior cingulate tracked value in terms of taste whereas left amygdala and left putamen were associated with choice. When primed with Health, right LPFC and posterior MOFC tracked value in terms of health. The findings contribute to the neural research on decision-making by demonstrating that changing perspectives can modulate value- and choice-related neural activity.     

Impaired fear extinction in adolescent rodents: Behavioural and neural analyses

Despite adolescence being a developmental window of vulnerability, up until very recently there were surprisingly few studies on fear extinction during this period. Here we summarise the recent work in this area, focusing on the unique behavioural and neural characteristics of fear extinction in adolescent rodents, and humans where relevant. A prominent hypothesis posits that anxiety disorders peak during late childhood/adolescence due to the non-linear maturation of the fear inhibition neural circuitry. We discuss evidence that impaired extinction retention in adolescence is due to subregions of the medial prefrontal cortex and amygdala mediating fear inhibition being underactive while other subregions that mediate fear expression are overactive. We also review work on various interventions and surprising circumstances which enhance fear extinction in adolescence. This latter work revealed that the neural correlates of extinction in adolescence are different to that in younger and older animals even when extinction retention is not impaired. This growing body of work highlights that adolescence is a unique period of development for fear inhibition.     

Neural systems implicated in delayed and probabilistic reinforcement.

This review considers the theoretical problems facing agents that must learn and choose on the basis of reward or reinforcement that is uncertain or delayed, in implicit or procedural (stimulus-response) representational systems and in explicit or declarative (action-outcome-value) representational systems. Individual differences in sensitivity to delays and uncertainty may contribute to impulsivity and risk taking. Learning and choice with delayed and uncertain reinforcement are related but in some cases dissociable processes. The contributions to delay and uncertainty discounting of neuromodulators including serotonin, dopamine, and noradrenaline, and of specific neural structures including the nucleus accumbens core, nucleus accumbens shell, orbitofrontal cortex, basolateral amygdala, anterior cingulate cortex, medial prefrontal (prelimbic/infralimbic) cortex, insula, subthalamic nucleus, and hippocampus are examined.     

Representations of motivational drives in mesial cortex,medial thalamus,hypothalamus and midbrain

We propose that neural representations of motivational drives, including sexual desire, hunger, thirst, fear, power-dominance, the motivational aspect of pain, the need for sleep, and nurturance, are represented in four areas in the brain. These are located in the medial hypothalamic/preoptic area, the periaqueductal gray matter (PAG) in the midbrain/pons, the midline and intralaminar thalamic nuclei, and in the anterior part of the mesial cortex, including the medial prefrontal and anterior cingulate areas. We attempt to determine the locations of each of these representations within the hypothalamus/preoptic area, periaqueductal gray and cortex, based on the available literature on activation of brain structures by stimuli that evoke these forms of motivation, on the effects of electrical and chemical stimulation and lesions of candidate structures, and on hodological data. We discuss the hierarchical organization of the representations for a given drive, outputs from these representations to premotor structures in the medulla, caudate-putamen, and cortex, and their contributions to involuntary, learned-sequential (operant) and voluntary behaviors.     

Adolescent gain in positive valence of a socially relevant stimulus: engagement of the mesocorticolimbic reward circuitry

A successful transition from childhood to adulthood requires adolescent maturation of social information processing. The neurobiological underpinnings of this maturational process remain elusive. This research employed the male Syrian hamster as a tractable animal model for investigating the neural circuitry involved in this critical transition. In this species, adult and juvenile males display different behavioral and neural responses to vaginal secretions, which contain pheromones essential for expression of sexual behavior in adulthood. These studies tested the hypothesis that vaginal secretions acquire positive valence over adolescent development via remodeling of neural circuits underlying sexual reward. Sexually naïve adult, but not juvenile, hamsters showed a conditioned place preference for vaginal secretions. Differences in behavioral response to vaginal secretions between juveniles and adults correlated with a difference in the vaginal secretion‐induced neural activation pattern in mesocorticolimbic reward circuitry. Fos immunoreactivity increased in response to vaginal secretions in the medial amygdala and ventral tegmental dopaminergic cells of both juvenile and adult males. However, only in adults was there a Fos response to vaginal secretions in non‐dopaminergic cells in interfascicular ventral tegmental area, nucleus accumbens core and infralimbic medial prefrontal cortex. These results demonstrate that a socially relevant chemosensory stimulus acquires the status of an unconditioned reward during adolescence, and that this adolescent gain in social reward is correlated with experience‐independent engagement of specific cell groups in reward circuitry.     

The angry brain: neural correlates of anger, angry rumination, and aggressive personality

Very little is known about the neural circuitry guiding anger, angry rumination, and aggressive personality. In the present fMRI experiment, participants were insulted and induced to ruminate. Activity in the dorsal anterior cingulate cortex was positively related to self-reported feelings of anger and individual differences in general aggression. Activity in the medial prefrontal cortex was related to self-reported rumination and individual differences in displaced aggression. Increased activation in the hippocampus, insula, and cingulate cortex following the provocation predicted subsequent self-reported rumination. These findings increase our understanding of the neural processes associated with the risk for aggressive behavior by specifying neural regions that mediate the subjective experience of anger and angry rumination as well as the neural pathways linked to different types of aggressive behavior.     

A [C]2-deoxyglucose analysis of the functional neural pathways of the limbic forebrain in the rat. IV. A pathway from the prefrontal cortical-medial thalamic system to the hypothalamus

The present study utilized the [¹⁴C]2-deoxyglucose (2-DG) cell labeling procedure to characterize a functional pathway from the prefrontal cortex (Pfc) and mediodorsal thalamic nucleus (MD) to the hypothalamus. Rats were injected with 2-DG prior to a 45 min experimental paradigm consisting of alternating 30 s on-off periods of electrical brain stimulation. Standard procedures were utilized for the removal and processing of brain tissue for X-ray autoradiography. In the first phase of this study, stimulation applied to the prefrontal cortex generally yielded a pattern of 2-DG distribution consistent with the findings of classical anatomical studies. Stimulation of the dorsomedial and ventromedial prefrontal cortex or the infralimbic cortex produced the most effective activation of the diencephalon. This activation was primarily limited to MD, with no involvement of any region of the hypothalamus. In the second phase of this study, brain regions activated following stimulation of sites along the rostro-caudal axis of MD were examined. Stimulation of MD resulted in the activation of the nucleus reuniens and other midline and non-specific thalamic nuclei. Stimulation of this nucleus also activated the ventromedial thalamic nucleus, medial aspects of the nucleus accumbens and the medial and sulcal prefrontal cortices. Again, in each of these cases, labeling within any region of the hypothalamus could not be detected. Since MD stimulation activated the midline thalamus, and the nucleus reuniens in particular, the last phase of this experiment involved stimulation of the nucleus reuniens in order to determine the source of medial thalamic inputs to the hypothalamus. Stimulation of the nucleus reuniens activated fibers which were distributed to both the medial and lateral hypothalamus. In addition, stimulation also activated the descending periventricular system, which could be followed to the level of the midbrain central gray and such limbic structures as the hippocampal formation, septal area, amygdala and prefrontal cortex. These findings indicate that Pfc-MD activation of the hypothalamus is achieved indirectly via interneurons within the nucleus reuniens.     

The neural basis of maternal responsiveness to infants: an fMRI study

Using fMRI, we examined the neural correlates of maternal responsiveness. Ten healthy mothers viewed alternating blocks of video: (i) 40 s of their own infant; (ii) 20 s of a neutral video; (iii) 40 s of an unknown infant and (iv) 20 s of neutral video, repeated 4 times. Predominant BOLD signal change to the contrasts of infants minus neutral stimulus occurred in bilateral visual processing regions (BA 19,21,37,38); to own infant minus unknown infant in right anterior temporal pole (BA 38), left amygdala and visual cortex (BA 19), and to the unknown infant minus own infant contrast in bilateral orbitofrontal cortex (BA 10,47) and medial prefrontal cortex (BA 8) [corrected] These findings suggest that amygdala and temporal pole may be key sites in mediating a mother's response to her infant and reaffirms their importance in face emotion processing and social behaviour.     

Depression‐related disturbances in rat maternal behaviour are associated with altered monoamine levels within mesocorticolimbic structures

The ability of mothers to sensitively attune their maternal responses to the needs of their developing young is fundamental to a healthy mother‐young relationship. The biological mechanisms that govern how mothers adjust caregiving to the dynamic changes in the demands of the young remain an open question. In the present study, we examined whether changes in monoamine levels, within discrete mesocorticolimbic structures involved in cognitive and motivational processes key to parenting, modulate this flexibility in caregiving across the postpartum period. The present study used a Wistar‐Kyoto (WKY) animal model of depression and control Sprague‐Dawley (SD) rats, which differ dramatically in their cognitive, motivational, and parenting performance. Levels of the monoamine neurotransmitters, dopamine, noradrenaline and serotonin, as well as their major metabolites, were measured within the medial prefrontal cortex, striatum, nucleus accumbens and medial preoptic area of SD and WKY mothers at early (postpartum day [PPD]7‐8), late (PPD15‐16) and weaning (PPD25) postpartum stages using high‐performance liquid chromatography with electrochemical detection. Consistent with our prior work, we find that caregiving of SD mothers declined as the postpartum period progressed. Relative to nulliparous females, early postpartum mothers had lower intracellular concentrations of monoamines, as well as lower noradrenaline turnover, and an elevated serotonin turnover within most structures. Postpartum behavioural trajectories subsequently corresponded to a progressive increase in all three monoamine levels within multiple structures. Compared to SD mothers, WKY mothers were inconsistent and disorganised in caring for their offspring and exhibit profound deficits in maternal behaviour. Additionally, WKY mothers had generally lower levels of all three monoamines, as well as different patterns of change across the postpartum period, compared to SD mothers, suggesting dysfunctional central monoamine pathways in WKY mothers as they transition and experience motherhood. Taken together, the results of the present study suggest a role for monoamines at multiple mesocorticolimbic structures with repect to modulating caregiving behaviours attuned to the changing needs of the young.