Gerd Poeggel

Maternal separation followed by early social deprivation affects the development of monoaminergic fiber systems in the medial prefrontal cortex of Octodon degus

The influence of early postnatal socio-emotional deprivation on the development of tyrosine hydroxylase- and 5-hydroxytryptamine-immunoreactive fiber innervation in the medial prefrontal cortex was quantitatively investigated in the precocial rodent Octodon degus. Forty-five-days-old degus from two groups were compared: (i) degus which were repeatedly separated from their mothers during the first three postnatal weeks and after weaning reared in complete isolation; and (ii) degus which were reared under normal undisturbed social conditions. The two monoaminergic fiber systems in the four subregions of the medial prefrontal cortex responded differentially to the deprivation. While the infralimbic cortex was the only subregion that displayed an increase in 5-hydroxytryptamine-positive fiber densities (129.2%) but no changes in tyrosine hydroxylase-immunoreactive fibers, the precentral medial (82.2%), anterior cingulate (74.6%) and prelimbic cortex (86.9%) showed significantly reduced tyrosine hydroxylase-positive fiber innervation, but no changes in 5-hydroxytryptamine-immunoreactive fiber densities. The number of tyrosine hydroxylase-positive somata in the ventral tegmental area and in the substantia nigra remained unchanged. In cortical areas the number of tyrosine hydroxylase-immunoreactive somata was increased (depending on the medial prefrontal cortex subregion between 241.8% and 398.7%) in deprived animals. This altered balance between the serotonergic and dopaminergic cortical innervation in the different subregions of the medial prefrontal cortex may reflect a counter-regulative anatomical and functional adaptation, which may be triggered by an altered activity of these transmitter systems during the phases of maternal separation and social isolation.

Juvenile emotional experience alters synaptic composition in the rodent cortex, hippocampus, and lateral amygdala

A quantitative anatomical study in the rodent anterior cingulate and somatosensory cortex, hippocampus, and lateral amygdala revealed region-, cell-, and dendrite-specific changes of spine densities in 3-week-old Octodon degus after repeated parental separation. In parentally separated animals significantly higher spine densities were found on the apical and basal dendrites of the cingulate cortex (up to 143% on apical and 138% on basal dendrite). Branching order analysis revealed that this effect is seen on all segments of the apical dendrite, whereas on the basal dendrites significantly higher spine densities were seen only on the outer branches (third to fifth dendritic segments). Increased spine densities were also observed on the hippocampal CA1 pyramidal neurons (up to 109% on the distal apical segments and up to 106% on the basal segment) compared with the control group. In contrast, significantly reduced spine densities were observed on the granule cell dendrites in the dentate gyrus (down to 92%) and on the apical dendrites in the medial nucleus of the amygdala (down to 95%). No significant changes of spine densities were seen in the somatosensory cortex (except for an increase in the proximal apical segments) and in the lateral nucleus of the dorsal amygdala (except for an increase in the proximal basal dendritic segments). These results demonstrate that repeated stressful emotional experience alters the balance of presumably excitatory synaptic inputs of pyramidal neurons in the limbic system. Such experience-induced modulations of limbic circuits may determine psychosocial and cognitive capacities during later life.

Early social deprivation alters monoaminergic afferents in the orbital prefrontal cortex of Octodon degus.

The influence of early parental deprivation on the development of tyrosine hydroxylase- and 5-hydroxytryptamine-immunoreactive fiber innervation of subregions of the orbital prefrontal cortex (ventrolateral orbital, lateral orbital and agranular insular cortex) was quantitatively investigated in the precocious lagomorph Octodon degus. Forty-five-day-old degus from two groups were compared: 1) degus which were repeatedly separated from their parents during the first three postnatal weeks, and after weaning they were reared in social isolation; and 2) degus which were reared undisturbed in their families. Compared with the normal control animals the ventrolateral orbital prefrontal cortex and agranular insular cortex of the deprived animals displayed significantly increased density of tyrosine hydroxylase-immunoreactive fibers (up to 172% in the ventrolateral orbital prefrontal cortex and up to 143% in the agranular insular cortex). The lateral orbital prefrontal cortex showed increased 5-hydroxytryptamine-positive fiber densities (up to 118%). This altered balance between the serotonergic and dopaminergic cortical innervation in the orbital prefrontal cortex may reflect an anatomical and functional adaptation, which may be triggered by an altered activity of these transmitter systems during the phases of parental separation and social isolation.

Imbalance of immunohistochemically characterized interneuron populations in the adolescent and adult rodent medial prefrontal cortex after repeated exposure to neonatal separation stress

Experimental studies in various animal models have revealed convincing evidence that stressful experience during early developmental periods produces a variety of behavioral, neuroanatomical and endocrine alterations, which are reminiscent of human mental disorders such as depression and various types of anxiety disorders. Since these mental disorders are assumed to be associated with altered GABAergic inhibition in cortical and subcortical brain regions, the current study tested the hypothesis that early postnatal adverse emotional experience (separation stress) interferes with the establishment and functional maturation of distinct inhibitory interneuron populations in different subregions of the medial prefrontal cortex (mPFC) of the precocious rodent degu (Octodon degus). At the age around puberty early stressed animals displayed significantly lower densities of calbindin-D28k-immunoreactive interneurons in the anterior cingulate (down to 79%) and in the precentral medial (down to 64%) subregions of the mPFC compared with age-matched unstressed controls. At this age the densities of two other interneuron types characterized by their expression of the calcium-binding proteins parvalbumin or calretinin remained at control levels. In adulthood, i.e. after an extended period without stress exposure, the density of calbindin-D28k-immunoreactive interneurons in the stressed animals was back to control numbers, whereas parvalbumin-immunoreactive interneurons displayed significantly elevated density in the anterior cingulate (up to 138%) and in the precentral medial cortex (up to 137%) of the stressed animals. In both age groups the density of calretinin- and corticotropin releasing hormone-immunoreactive interneurons did not differ between stressed and control animals, and the prelimbic and infralimbic subregions of the medial prefrontal cortex remained unaffected by stress experience. These results confirm that early adverse emotional experience induces long lasting age-, region- and neuron-specific imbalance of inhibitory systems in some, but not all subregions of the medial prefrontal cortex of the degu.

Early auditory filial learning in degus (Octodon degus): behavioral and autoradiographic studies

Degu mothers (Octodon degus) utter specific maternal calls during nursing which presumably stimulate and reinforce suckling. Pups from surgically muted mothers show a reduced gain of body weight during postnatal development compared to pups from normally vocalizing mothers. Our behavioral studies suggest that the pups have to learn the meaning of the maternal calls during the first two weeks of life. Two-week-old pups from normally vocalizing mothers expressed a preference for the maternal call in a behavioral discrimination test, in contrast to pups from surgically muted mothers. Investigation of brain activities using the 2-[14C]fluoro-deoxyglucose (2-FDG) method revealed that pups from normal mothers display a significantly higher 2-FDG uptake in precentral medial, anterior cingulate cortex and a slight, non-significant increase in the prelimbic cortex and orbital PFC upon presentation of the maternal call, compared to pups from muted mothers, for which the maternal call was unfamiliar and meaningless. These prefrontal cortical areas are known to be involved in associative learning processes and our data suggest that they are involved in the association between the maternal call and the positive emotional situation during nursing.

Early neonatal and postweaning social emotional deprivation interferes with the maturation of serotonergic and tyrosine hydroxylase-immunoreactive afferent fiber systems in the rodent nucleus accumbens, hippocampus and amygdala.

The impact of early emotional experience on the development of serotonergic and dopaminergic fiber innervation of the nucleus accumbens, hippocampal formation and the amygdala was quantitatively investigated in the precocious rodent Octodon degus. Two animal groups were compared: 1) degus which were repeatedly separated from their parents during the first three postnatal weeks, after weaning they were individually reared in chronic social isolation and 2) controls which were reared undisturbed with their families. In the deprived animals 5-hydroxytryptamine-immunoreactive fiber densities were increased in the core region of the nucleus accumbens (up to 126%), in the central nucleus of the amygdala (up to 112%) and in the outer subregion of the dentate gyrus stratum moleculare (up to 149%), whereas decreased fiber densities were detected in the dentate subgranular layer (down to 86%) and in the stratum lacunosum of the hippocampal cornu ammonis region 1 (down to 86%). Tyrosine hydroxylase-immunoreactive fiber densities were increased in the core (up to 115%) and shell region (up to 113%) of the nucleus accumbens of deprived animals, whereas decreased fiber densities (down to 84%) were observed in the hilus of the dentate gyrus. In the stratum granulosum and subgranular layer the fiber densities increased up to 168% and 127% respectively. In summary, these results indicate that the postnatal establishment of the monoaminergic innervation of limbic areas is modulated in response to early emotional experience, and that this environmental morphological adaptation is highly region specific.

Mother's voice buffers separation-induced receptor changes in the prefrontal cortex of Octodon degus

Although the potential vulnerability of the postnatally developing brain toward adverse environmental influences is generally recognized, relatively little is known about the basic mechanisms involved. The plasticity and adaptability of the postnatally developing brain in response to adverse emotional experiences was analyzed in the South American Octodon degus. Our study revealed that repeated brief separation from the parents and exposure to an unfamiliar environment induces an up-regulation of dopamine (D1) and 5-hydroxytrytamine (5HT1(A))-receptor density in the precentral medial, anterior cingulate, prelimbic and infralimbic cortices in female pups. No significant changes of gamma aminobutyric acid (GABA(A)) receptor density were found in deprived animals of both genders. The acoustic presence of the mother during parental separation suppressed the D1-receptor up-regulation as well as the 5-HT1(A)-receptor up-regulation, again only in the female pups. These results demonstrate that that early adverse emotional experience alters aminergic function within the prefrontal cortex in the female but not the male brain. The mothers voice, a powerful emotional signal, can protect the developing cortex from separation-induced receptor changes.

Recognition of Mother's voice evokes metabolic activation in the medial prefrontal cortex and lateral thalamus of Octodon degus pups

In a variety of animal species, including primates, vocal communication is an essential part to establish and maintain social interactions, including the emotional bond between the newborn, its parents and siblings. The aim of this study in pups of the trumpet-tailed rat, Octodon degus, was to identify cortical and subcortical brain regions, which are involved in the perception of vocalizations uttered by the mother. In this species, which is characterized by an elaborated vocal repertoire, the (14C)-2-fluoro-deoxyglucose autoradiography was applied to measure region-specific metabolic activation in response to the presentation of a learned emotionally relevant acoustic stimulus, the maternal calls. Already at the age of eight days the precentral medial cortex, anterior cingulate cortex and the lateral thalamus could be identified by their enhanced metabolic activation in response to the presentation of the emotionally relevant maternal nursing calls, whereas other brain areas, such as the hippocampus and amygdala did not show stimulus-induced activation. Since in humans changes of activity patterns in relation to the emotional content of spoken language have been observed in similar brain regions, e.g. in the anterior cingulate cortex, Octodon degus may provide a suitable animal model to study the cellular and synaptic mechanisms underlying perception, production and processing of conspecific vocalizations.

Repeated neonatal separation stress alters the composition of neurochemically characterized interneuron subpopulations in the rodent dentate gyrus and basolateral amygdala.

Emotional experience during early life has been shown to interfere with the development of excitatory synaptic networks in the prefrontal cortex, hippocampus, and the amygdala of rodents and primates. The aim of the present study was to investigate a developmental “homoeostatic synaptic plasticity” hypothesis and to test whether stress‐induced changes of excitatory synaptic composition are counterbalanced by parallel changes of inhibitory synaptic networks. The impact of repeated early separation stress on the development of two GABAergic neuronal subpopulations was quantitatively analyzed in the brain of the semiprecocial rodent Octodon degus. Assuming that PARV‐ and CaBP‐D28k‐expression are negatively correlated to the level of inhibitory activity, the previously described reduced density of excitatory spine synapses in the dentate gyrus of stressed animals appears to be “amplified” by elevated GABAergic inhibition, reflected by reduced PARV‐ (down to 85%) and CaBP‐D28k‐immunoreactivity (down to 74%). In opposite direction, the previously observed elevated excitatory spine density in the CA1 region of stressed animals appears to be amplified by reduced inhibition, reflected by elevated CaPB‐D28k‐immunoreactivity (up to 149%). In the (baso)lateral amygdala, the previously described reduction of excitatory spine synapses appears to be “compensated” by reduced inhibitory activity, reflected by dramatically elevated PARV‐ (up to 395%) and CaPB‐D28k‐immunoreactivity (up to 327%). No significant differences were found in the central nucleus of the amygdala, the piriform, and somatosensory cortices and in the hypothalamic paraventricular nucleus. Thus during stress‐evoked neuronal and synaptic reorganization, a homeostatic balance between excitation and inhibition is not maintained in all regions of the juvenile brain.

Paternal Deprivation Affects the Development of Corticotrophin-Releasing Factor-Expressing Neurones in Prefrontal Cortex, Amygdala and Hippocampus of the Biparental Octodon degus

Although the critical role of maternal care on the development of brain and behaviour of the offspring has been extensively studied, knowledge about the importance of paternal care is comparatively scarce. In biparental species, paternal care significantly contributes to a stimulating socio‐emotional family environment, which most likely also includes protection from stressful events. In the biparental caviomorph rodent Octodon degus, we analysed the impact of paternal care on the development of neurones in prefrontal‐limbic brain regions, which express corticotrophin‐releasing factor (CRF). CRF is a polypeptidergic hormone that is expressed and released by a neuronal subpopulation in the brain, and which not only is essential for regulating stress and emotionality, but also is critically involved in cognitive functions. At weaning age [postnatal day (P)21], paternal deprivation resulted in an elevated density of CRF‐containing neurones in the orbitofrontal cortex and in the basolateral amygdala of male degus, whereas a reduced density of CRF‐expressing neurones was measured in the dentate gyrus and stratum pyramidale of the hippocampal CA1 region at this age. With the exception of the CA1 region, the deprivation‐induced changes were no longer evident in adulthood (P90), which suggests a transient change that, in later life, might be normalised by other socio‐emotional experience. The central amygdala, characterised by dense clusters of CRF‐immunopositive neuropil, and the precentral medial, anterior cingulate, infralimbic and prelimbic cortices, were not affected by paternal deprivation. Taken together, this is the first evidence that paternal care interferes with the developmental expression pattern of CRF‐expressing interneurones in an age‐ and region‐specific manner.