Marilyn J. Numan

Axon-sparing lesions of the preoptic region and substantia innominata disrupt maternal behavior in rats

In this study we investigated the effects of axon-sparing lesions of the preoptic region on the maternal behavior of postpartum rats. The lesions were produced with the excitotoxic amino acid N-methyl-D,L-aspartic acid (NMA). The first experiment determined that bilateral injections of NMA into the medial preoptic area (MPOA) of fully maternal lactating rats disrupted maternal behavior. In a second experiment, bilateral injections of NMA into the lateral preoptic area and adjoining substantia innominata (LP/SI region) also disrupted maternal behavior. A third experiment, employing horseradish peroxidase histochemistry, provided anatomical evidence that NMA destroys neuronal cell bodies while sparing fibers of passage. These findings were discussed with respect to the view that an MPOA-to-LP/SI-to-ventral tegmental area circuit underlies maternal behavior in the rat.

A lesion and neuroanatomical tract-tracing analysis of the role of the bed nucleus of the stria terminalis in retrieval behavior and other aspects of maternal responsiveness in rats

The ventral part of the bed nucleus of the stria terminalis forms a junctional region between the medial and lateral preoptic areas. Previous work has shown that the neurons in this region express Fos-like immunoreactivity during maternal behavior, suggesting their involvement in maternal behavior control. Supporting this hypothesis, the first experiment shows that excitotoxic amino acid lesions of the bed nucleus of the stria terminalis disrupt retrieval behavior and other aspects of maternal responsiveness in postpartum rats. The second study traces the efferent projections of the ventral bed nucleus with the anterograde tracer Phaseolis vulgaris leucoagglutinin. The following regions receive strong projections: lateral septum, substantia innominata, paraventricular hypothalamic nucleus, ventral premammillary nucleus, supramammillary nucleus, paraventricular thalamus, ventral tegmental area, periaqueductal gray, retrorubral field, and the region surrounding the locus coeruleus.

Expression of Fos-like immunoreactivity in the preoptic area of maternally behaving virgin and postpartum rats.

This study uses Fos immunocytochemistry to show that the medial preoptic area and ventral bed nucleus of the stria terminalis are activated in maternally behaving female rats. In Experiment 1, virgin female rats that showed maternal behavior toward pups had more cells in these regions that expressed Fos-like immunoreactivity than did virgin females that were not maternally responsive. In Experiment 2, postpartum rats that were exposed to pups and showed maternal behavior had more Fos-labeled cells in these regions than did postpartum rats exposed to candy. Evidence also indicated that functional modifications in the medial amygdala were related to the changes in Fos expression observed in the preoptic area and ventral bed nucleus of the stria terminalis.

The effects of D1 or D2 dopamine receptor antagonism in the medial preoptic area, ventral pallidum, or nucleus accumbens on the maternal retrieval response and other aspects of maternal behavior in rats

The medial preoptic area (MPOA), ventral pallidum (VP), and nucleus accumbens (NA) receive dopaminergic afferents and are involved in maternal behavior. Experiments investigated whether dopamine (DA) receptor antagonism in NA disrupts maternal behavior, determined the type of DA receptor involved, and investigated the involvement of drug spread to VP or MPOA. Injection of SCH 23390 (D1 DA receptor antagonist) into NA of postpartum rats disrupted retrieving at dosage levels that were ineffective when injected into MPOA or VP. Motor impairment was not the cause of the deficit. Injection of eticlopride (D2 DA receptor antagonist) into NA or VP was without effect. Results emphasize the importance of DA action on D1 receptors in NA for retrieval behavior.

Importance of pup-related sensory inputs and maternal performance for the expression of Fos-like immunoreactivity in the preoptic area and ventral bed nucleus of the stria terminalis of postpartum rats.

This study used Fos immunocytochemistry to locate neurons within the medial preoptic area (MPOA) and ventral bed nucleus of the stria terminalis (VBNST) that are tightly associated with the performance of maternal behavior in postpartum rats. In the first experiment, a high degree of Fos activation was observed in these regions if females were allowed to interact fully with pups, but not if they could receive only olfactory, visual, and auditory inputs from pups. The second experiment found that olfactory bulbectomy combined with thelectomy did not eliminate Fos expression in the MPOA and VBNST of females displaying maternal behavior. These Fos-expressing neurons may represent efferent neurons essential for the performance of maternal behavior.

Evidence that the medial amygdala projects to the anterior/ventromedial hypothalamic nuclei to inhibit maternal behavior in rats

The maternal behaviors shown by a rat that has given birth are not shown by a virgin female rat when she is first presented with young. This absence of maternal behavior in virgins has been attributed to the activity of a neural circuit that inhibits maternal behavior in nulliparae. The medial amygdala and regions of the medial hypothalamus such as the anterior and ventromedial hypothalamic nuclei have previously been shown to inhibit maternal behavior, in that lesions to these regions promote maternal responding. Furthermore, we have recently shown that these and other regions, such as the principal bed nucleus of the stria terminalis, the ventral lateral septum, and the dorsal premammillary nucleus, show higher pup-induced Fos-immunoreactivity in non-maternal rats exposed to pups than during the performance of maternal behavior, indicating that they too could be involved in preventing maternal responsiveness. The current study tested whether the medial amygdala projects to the anterior/ventromedial hypothalamic nuclei in a neural circuit that inhibits maternal behavior, as well as to see what other brain regions could participate in this circuit. Bilateral excitotoxic lesions of the medial amygdala, or of the anterior/ventromedial hypothalamic nuclei, promoted maternal behavior. Unilateral medial amygdala lesions caused a reduction of pup-induced Fos-immunoreactivity in the anterior/ventromedial hypothalamic nuclei in non-maternal rats ipsilateral to the lesion, as well as in the principal bed nucleus of the stria terminalis, ventral lateral septum, and dorsal premammillary nucleus. Finally, unilateral medial amygdala lesions paired with contralateral anterior/ventromedial hypothalamic nuclei lesions promoted maternal behavior, although ipsilateral lesion placements were also effective.Together, these results indicate that the medial amygdala projects to the anterior/ventromedial hypothalamic nuclei in a neural circuit that inhibits maternal behavior, and that the principal bed nucleus of the stria terminalis, ventral lateral septum, and dorsal premammillary nucleus could also be involved in this circuit.

Projection Sites of Medial Preoptic Area and Ventral Bed Nucleus of the Stria Terminalis Neurons that Express Fos during Maternal Behavior in Female Rats

Medial preoptic area (MPOA) and ventral bed nucleus of the stria terminalis (VBST) neurons are involved in maternal behavior, but the neural sites to which the maternally relevant neurons project have not been determined. Since MPOA and VBST neurons express Fos during maternal behavior, we used a double‐labeling immunocytochemical procedure to detect both Fos and a retrograde tracer, wheat germ agglutinin (WGA), in order to determine where these Fos neurons project. On Day 4 postpartum, fully maternal females were separated from their litters. On Day 5, WGA was iontophoretically injected into one of the following regions known to receive MPOA and/or VBST input: Lateral septum, medial hypothalamus at the level of the ventromedial nucleus, lateral habenula, ventral tegmental area, retrorubral field, or periaqueductal gray. On Day 7, females received a 2‐h test with either pups or candy, after which they were perfused and their brains were processed for the detection of Fos and WGA. As expected, females tested with pups had more Fos‐containing neurons in the MPOA and VBST than did females tested with candy. After WGA injections into several brain sites, the number of double‐labeled cells observed in the MPOA and VBST was greater for the maternal females when compared to the non‐maternal females. Therefore, these results pinpointed neural circuits that were activated during maternal behavior. For the maternal females, Fos‐containing neurons in the MPOA projected most strongly to the medial hypothalamus at the level of the ventromedial nucleus and to the lateral septum, while Fos‐containing neurons in the VBST projected most strongly to the retrorubral field, ventral tegmental area, and medial hypothalamus. Although relatively few MPOA and VBST neurons which expressed Fos during maternal behavior projected to the periaqueductal gray, these Fos‐expressing neurons made up a relatively large proportion of the MPOA and VBST projection to the periaqueductal gray. This study suggests that MPOA and VBST efferents project to a variety of regions to promote full maternal responsiveness.

A functional neuroanatomical investigation of the role of the medial preoptic area in neural circuits regulating maternal behavior

The medial preoptic area (MPOA) is essential for normal maternal behavior in the rat. Hormone stimulation of the MPOA facilitates the behavior and lesions of the MPOA and the adjoining ventral part of the bed nucleus of the stria terminalis (vBST) disrupt the behavior. The MPOA/vBST also show increases in Fos protein expression during maternal behavior. The present study examines the larger neural circuitry within which the MPOA/vBST might operate to influence maternal behavior. Combining Fos immunocytochemistry with unilateral excitotoxic amino acid lesions or lateral knife cuts of the MPOA/vBST, we sought to identify brain regions which might be under the influence of Fos expressing neurons in the MPOA/vBST. Two brain regions, the shell of the nucleus accumbens (NAs), and the intermediate part of the lateral septum (LSi) were identified. Both the NAs and LSi exhibited elevated Fos expression during maternal behavior, while unilateral MPOA/vBST damage resulted in an ipsilateral reduction of maternal behavior-induced Fos expression in each area, suggesting that MPOA/vBST neurons modulate Fos expression and associated neural activity in both of these structures during maternal behavior. Importantly, these unilateral preoptic lesions also depressed maternal behavior-induced Fos expression in the ipsilateral MPOA and vBST. The effects of these lesions on Fos expression in the periaqueductal gray (PAG) and other brain regions are also presented.

Using c-Fos immunocytochemistry to identify forebrain regions that may inhibit maternal behavior in rats.

Evidence indicates there is a neural system that inhibits maternal behavior in virgin rats. It has been suggested that pregnancy hormones promote the onset of maternal behavior by reducing the behavioral influence of this system. The authors used c-Fos immunocytochemistry to identify brain regions more activated by pup exposure in nonmaternal rats than in maternal rats. Previous experiments indicated that some of these regions, such as the posterodorsal medial amygdala and several medial hypothalamic sites, inhibit maternal behavior. For others, such as the ventral lateral septum, dorsal premammillary nucleus, and principal bed nucleus of the stria terminalis, this is the first indication that they could also inhibit maternal responding. These regions have previously been implicated in promoting defensive behaviors, consistent with the finding that nonmaternal rats actively avoid pups. These findings suggest the existence of a neural circuit through which pup exposure could promote defensive responses in virgin rats, and how pregnancy hormones could reduce such activity to stimulate maternal behavior.

Medial preoptic area interactions with the nucleus accumbens–ventral pallidum circuit and maternal behavior in rats

Several experiments explored the roles of nucleus accumbens (NA), ventral pallidum (VP) and medial preoptic area (MPOA) in the regulation of maternal behavior in rats. A preliminary experiment found that bilateral radiofrequency lesions of medial NA did not disrupt maternal behavior. Experiment 1 found that bilateral infusions of muscimol into VP, but not into medial NA, reversibly disrupted maternal behavior. Experiment 2 found that unilateral muscimol injections into VP disrupted maternal behavior to a greater extent when paired with a contralateral N-methyl-d-aspartic acid (NMDA) MPOA lesion than when paired with a sham MPOA lesion. Experiment 3 showed that a unilateral NMDA MPOA lesion paired with a contralateral NMDA VP lesion (Contra group) disrupted maternal behavior to a much greater extent than did sham NMLA lesions or NMDA lesions of MPOA and VP ipsilateral to one another. Experiment 3 focused on the specificity of the maternal behavior disruptions and found that the primary maternal deficit in the Contra females was a severe deficit in retrieval behavior. Importantly, these females showed normal hoarding behavior, home cage activity, and elevated plus maze activity. Experiment 3 used Neu N immunohistochemistry to define the extent of MPOA and VP excitotoxic lesions. It is hypothesized that MPOA acts to facilitate the active components of maternal behavior by inhibiting NA, which then releases VP from GABAergic inhibition, and such disinhibition of VP allows pup stimuli to trigger appropriate maternal responses.