Neocortical neuronal morphology in the Siberian Tiger (Panthera tigris altaica) and the clouded leopard (Neofelis nebulosa)

Despite extensive investigations of the neocortex in the domestic cat, little is known about neuronal morphology in larger felids. To this end, the present study characterized and quantified the somatodendritic morphology of neocortical neurons in prefrontal, motor, and visual cortices of the Siberian tiger (Panthera tigris altaica) and clouded leopard (Neofelis nebulosa). After neurons were stained with a modified Golgi technique (N = 194), dendritic branching and spine distributions were analyzed using computer‐assisted morphometry. Qualitatively, aspiny and spiny neurons in both species appeared morphologically similar to those observed in the domestic cat. Although the morphology of spiny neurons was diverse, with the presence of extraverted, inverted, horizontal, and multiapical pyramidal neurons, the most common variant was the typical pyramidal neuron. Gigantopyramidal neurons in the motor cortex were extremely large, confirming the observation of Brodmann ([1909] Vergleichende Lokalisationlehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig, Germany: J.A. Barth), who found large somata for these neurons in carnivores in general, and felids in particular. Quantitatively, a MARSplines analysis of dendritic measures differentiated typical pyramidal neurons between the Siberian tiger and the clouded leopard with 93% accuracy. In general, the dendrites of typical pyramidal neurons were more complex in the tiger than in the leopards. Moreover, dendritic measures in tiger pyramidal neurons were disproportionally large relative to body/brain size insofar as they were nearly as extensive as those observed in much larger mammals (e.g., African elephant). Comparison of neuronal morphology in a more diverse collection of larger felids may elucidate the comparative context for the relatively large size of the pyramidal neurons observed in the present study. J. Comp. Neurol. 524:3641–3665, 2016. © 2016 Wiley Periodicals, Inc.     

The morphological changes of pyramidal and spiny stellate cells in the primary visual cortex of chronic morphine treated cats

Morphine exposure may have a negative effect on the receptive field properties of neurons in primary visual cortex of cats. The present experiment used morphological methods in order to investigate whether chronic morphine treatment also affects dendritic characters of these neurons. According to the Sholl analysis and dendritic branch order analysis, we obtained the dendritic length and calculated the spine density on dendrites of the pyramidal neurons in layer III and the spiny stellate neurons in layer IV. The results showed that morphine exposure induced significant decreases in the total dendritic length and spine density on both pyramidal and spiny stellate neurons. The further branch order analysis revealed that spine density was decreased at every (first to fourth) branch order of dendrites of pyramidal and spiny stellate neurons. Decrease in dendritic length of the pyramidal neurons was observed only at the fourth branch order, while the spiny stellate neurons had shorter dendrite at the second and third branch order. These findings may underlie the degradation of receptive field properties of the primary visual cortex neurons following chronic morphine exposure.     

Dendritic morphology on neurons from prefrontal cortex, hippocampus, and nucleus accumbens is altered in adult male mice exposed to repeated low dose of malathion

Malathion is a highly neurotoxic pesticide widely used in daily life. Acute and chronic toxicity from this organophosphorus compound may cause damage to health, especially to the central nervous system. In the present work, we show the effects of chronic exposure of malathion on dendritic morphology of neurons from prefrontal cortex (PFC), hippocampus, and nucleus accumbens (NAcc) in adult male mice. Animals were injected i.p. with low dose of malathion (40 mg/kg body weight) for 14 days. Control animals were injected with corn oil, used as vehicle. Fourteen days after the last injection, brains were removed and processed by the Golgi-Cox stain method, and coronal sections were obtained to perform Sholl analysis on pyramidal neurons from the PFC, CA1 area from the hippocampus, and medium spiny cells from the NAcc. Dendritic morphology analysis included the total dendritic length, the maximum branching order, and the dendritic spine density. Results indicated a significant decrement on dendritic morphology in neurons from the hippocampus and the PFC in animals injected with malathion, whereas medium spiny neurons from NAcc showed a significant decrement only on the dendritic spine density in malathion injected mice, as compared to control mice. These results suggest that chronic toxicity of malathion alters the dendritic morphology in adult age, which may affect behavior.     

Target-specific differences in somatodendritic morphology of layer V pyramidal neurons in rat motor cortex

Dendritic geometry has been shown to be a critical determinant of information processing and neuronal computation. However, it is not known whether cortical projection neurons that target different subcortical nuclei have distinct dendritic morphologies. In this study, fast blue retrograde tracing in combination with intracellular Lucifer yellow injection and diaminobenzidine (DAB) photoconversion in fixed slices was used to study the morphological features of corticospinal, corticostriatal, and corticothalamic neurons in layer V of rat motor cortex. Marked differences in the distribution of soma, somal size, and dendritic profiles were found among the three groups of pyramidal neurons. Corticospinal neurons were large, were located in deep layer V, and had the most expansive dendritic fields. The apical dendrites of corticospinal pyramidal neurons were thick, spiny, and branched. In contrast, nearly all corticostriatal neurons were small cells located in superficial layer V. Their apical dendritic shafts were significantly more slender, though spiny like those of corticospinal neurons. Corticothalamic neurons, which were located in superficial layer V and in layer VI, had small or medium-sized soma, slender apical dendritic shafts, and dendrites that were largely spine free. This study indicates that, in layer V of rat motor cortex, each population of projection neurons has a unique somatodendritic morphology and suggests that distinct modes of cortical information processing are operative in corticospinal, corticostriatal, and corticothalamic neurons.     

Prenatal development of neurons in the human prefrontal cortex: I. A qualitative Golgi study

Golgi-Stensaas and rapid-Golgi staining techniques are used to study neuronal differentiation in the developing human prefrontal cortex in fetuses, premature infants, and full-term newborns from 10.5 to 40 weeks of gestation. Horizontal neurons (Cajal-Retzius neurons) above the cortical plate (in the marginal zone) and randomly oriented neurons below the cortical plate (in the primordial subplate) are more differentiated than the immature bipolar cortical plate neurons in the 10.5-week fetus. During 13.5-15 weeks of gestation the fetal subplate zone can be clearly distinguished-between the cortical plate and the intermediate zone. This subplate zone contains more mature neurons than the cortical plate, especially polymorphous neurons. The basic features of the apical and basal dendrites of pyramidal neurons develop between 17 and 25 weeks of gestation, before the thalamocortical fibres invade the cortical plate. Intensive differentiation of the subplate neurons occurs in this period, when various types of afferent fibres reside in the subplate zone. At least five neuronal types can be distinguished in the subplate, i.e., polymorphous, fusiform, multipolar, normal, and inverted pyramidal neurons. The ingrowth of afferent fibres into the cortical plate between 26 and 34 weeks of gestation coincides with intensive dendritic differentiation and the appearance of spines on dendrites of the prospective layer III and V pyramidal neurons as well as with the differentiation of the double bouquet interneurons in the prospective supragranular layers and layer IV. Multipolar nonpyramidal neurons with the dendritic features of basket neurons are observed between 32 and 34 weeks of gestation in future layer V. They are less differentiated than the double bouquet neurons. The neurons of the subplate zone continue their dendritic differentiation after 26/27 weeks of gestation and are still observed in the full-term newborn. The axonal pattern of the subplate neurons suggests a possible functional role for them as either interneurons or projection neurons.     

Development of spiny and aspiny neurons in the caudate nucleus of the dog during the first postnatal month

The adult and developmental morphology of spiny and aspiny neurons in the dog caudate nucleus was examined using the Golgi-Kopsch technique. In the adult, three types each of spiny and aspiny neurons were identified based upon dendritic morphology and cell soma size. They corresponded in large part to those neurons described previously in the caudate nuclei of the rat, cat, and monkey. At birth, dendrites of spiny neurons possessed varicosities, filopodia, and thick proximal dendritic stumps—all characteristic of immaturity. Maturation of these processes involved the thinning of proximal dendrites, lengthening of dendritic shafts, and growth of dendritic spines. Although most of the dendritic maturation occurred during the first postnatal month, spine densities and dendritic lengths of spiny I neurons at 30 days were still less than those seen in the adult. Aspiny I neurons were also immature at birth but lacked the filopodia and thicker proximal dendrites that characterized immature spiny neurons. Aspiny dendritic development involved primarily the lengthening of dendritic processes; by 30 days the aspiny I neurons were indistinguishable from those seen in the adult. These results suggest that dendritic development of spiny I neurons may extend well past the end of the first postnatal month and that studies investigating functional development in the caudate nucleus should consider the relatively extended time period required for maturation of these primary synaptic sites.     

Decreased dendritic spine density of neurons of the prefrontal cortex and nucleus accumbens and enhanced amphetamine sensitivity in postpubertal rats after a neonatal amygdala lesion

A neonatal basolateral‐amygdala (nBLA) lesion in rats could be a potential animal model to study the early neurodevelopmental abnormalities associated with the behavioral and morphological brain changes observed in schizophrenia. Morphological alterations in pyramidal neurons from the prefrontal cortex (PFC) have been observed in postmortem schizophrenic brains, mainly because of decreased dendritic arbor and spine density. We assessed the effects of nBLA‐lesion on the dendritic morphology of neurons from the PFC and the nucleus accumbens (NAcc) in rats. nBLA lesions were made on postnatal day 7 (PD7), and later, the dendritic morphology was studied by the Golgi‐Cox stain procedure followed by Sholl analysis at PD35 (prepubertal) and PD60 (adult) ages. We also evaluated the effects of the nBLA‐lesion on locomotor activity caused by a novel environment, apomorphine, and amphetamine. Adult animals with nBLA lesions showed a decreased spine density in pyramidal neurons from the PFC and in medium spiny cells from the NAcc. An increased locomotion in a novel environment and in amphetamine‐treated adult animals with an nBLA‐lesion was observed. Our results indicate that nBLA‐lesion alters the neuronal dendrite morphology of the NAcc and PFC, suggesting a disconnection between these limbic structures. The locomotion paradigms support the idea that dopaminergic transmission is altered in the nBLA lesion model. This could help to understand the consequences of an earlier amygdala dysfunction in schizophrenia. Synapse 63:1143–1153, 2009. © 2009 Wiley‐Liss, Inc.     

Ontogeny of altered dendritic morphology in the rat prefrontal cortex, hippocampus, and nucleus accumbens following Cesarean delivery and birth anoxia

We used a delayed Cesarean birth model and the Golgi-Cox staining method to investigate the effects of perinatal anoxia on prefrontal cortex (PFC) and hippocampal (CA1) pyramidal neurons as well as nucleus accumbens (NAcc) medium spiny neurons. Dendritic morphology in these regions was studied on postnatal days (P) 2, 7, 14, 21, 35, and 70 in male Sprague-Dawley rats born either vaginally (VAG) or by Cesarean section either with (C + anoxia) or without (C-only) anoxia. The most striking birth group differences seen were at the level of dendritic spine densities on P35. During this postnatal period the dendritic spine density of PFC neurons was significantly lower in C + anoxia and C-only animals than in VAG controls; however, by P70 PFC spine densities in all birth groups were comparable. In contrast, hippocampal spine densities on P35 were comparably greater in C + anoxia animals than in VAG controls, whereas in C-only animals spine densities were lower than controls; here again, by P70 all groups had comparable hippocampal spine densities. In NAcc greater spine densities were seen on medium spiny neurons of C + anoxia animals on P35. These findings provide evidence that perinatal insult in the form of Cesarean birth with or without anoxia alters the dendritic development of PFC and hippocampal pyramidal neurons and to some extent also of NAcc medium spiny neurons. They also suggest that perinatal anoxia can alter the neuronal development of key structures thought to be affected in such late-onset dopamine-related disorders as schizophrenia and Attention Deficit Hyperactivity Disorder (ADHD).     

Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring

Prenatal stress alters neuronal morphology of mesocorticolimbic structures such as frontal cortex and hippocampus in the adult offspring. We investigated here the effects of prenatal stress on the spine density and the dendrite morphology of hippocampal pyramidal neurons and medium spiny cells from nucleus accumbens in prepubertal and adult male offsprings. Sprague‐Dawley pregnant dams were stressed by restraining movement daily for 2 hours from gestational day 11 until delivery. Control mothers remained free in their home cage without water and food during the stressful event. Male offsprings from immobilized and control rats were left to grow until postnatal day (PD) 35 for the prepubertal group, and until PD 65 for the adult group. Spontaneous locomotor activity was assessed and then brains were removed to study the dendritic morphology by the Golgi‐Cox stain method followed by Sholl analysis. Prenatally stressed animals demonstrated increased locomotion and alterations in spine density in the hippocampus and nucleus accumbens at both ages. However, prepubertal males showed an increase in spine density in the CA1 hippocampus with a decrease in CA3 hippocampus, whereas the adult group showed a decrease in the spine density in both of the regions studied. These results suggest that prenatal stress carried out during the middle of pregnancy affect the spine density and basal dendrites of pyramidal neurons of hippocampus, as well as the dendritic morphology of nucleus accumbens which may reflect important changes in the mesocorticolimbic dopaminergic transmission and behaviors associated with the development of psychiatric diseases such as schizophrenia. Synapse 63:794–804, 2009. © 2009 Wiley‐Liss, Inc.     

Dendritic morphology changes in neurons from the ventral hippocampus,amygdala and nucleus accumbens in rats with neonatal lesions into the prefrontal cortex

Neonatal prefrontal cortex (nPFC) lesions in rats could be a potential animal model to study the early neurodevelopmental abnormalities associated with the behavioral and morphological brain changes observed in schizophrenia. Morphological alterations in pyramidal neurons from the ventral hippocampus (VH) have been observed in post‐mortem schizophrenic brains, mainly because of decreased dendritic arbor and spine density. We assessed the effects of nPFC‐lesions on the dendritic morphology of neurons from the VH, basolateral‐amygdala (BLA) and the nucleus accumbens (NAcc) in rats. nPFC lesions were made on postnatal day 7 (PD7), after dendritic morphology was studied by the Golgi‐Cox stain procedure followed by Sholl analysis at PD35 (prepubertal) and PD60 (adult) ages. We also evaluated the effects of PFC‐lesions on locomotor activity caused by a novel environment. Adult animals with nPFC lesions showed a decreased spine density in pyramidal neurons from the VH and in medium spiny cells from the NAcc. An increased locomotion was observed in a novel environment for adult animals with a PFC‐lesion. Our results indicate that PFC‐lesions alter the neuronal dendrite morphology of the NAcc and the VH, suggesting a disconnection between these limbic structures. The locomotion paradigms suggest that dopaminergic transmission is altered in the PFC lesion model. This could help to understand the consequences of an earlier PFC dysfunction in schizophrenia. To evaluate possible dendritic changes in neonatal prefrontal cortex lesions in schizophrenia‐related regions including nucleus accumbens, ventral hippocampus and basolateral amygdala, we used the Golgi‐Cox stain samples at PD35 and PD70. Our results suggest that neonatal prefrontal cortex damage alters dendritic parameters in limbic regions, and this has potential implications for schizophrenia. Synapse 69:314–325, 2015 . © 2015 Wiley Periodicals, Inc.     

Carboxypeptidase E knockout mice exhibit abnormal dendritic arborization and spine morphology in central nervous system neurons

Carboxypeptidase E (CPE) is involved in maturation of neuropeptides and sorting of brain‐derived neurotrophic factor (BDNF) to the regulated pathway for activity‐dependent secretion from CNS neurons. CPE knockout (CPE‐KO) mice have many neurological deficits, including deficits in learning and memory. Here, we analyzed the dendritic arborization and spine morphology of CPE‐KO mice to determine a possible correlation of defects in such structures with the neurological deficits observed in these animals. Analysis of pyramidal neurons in layer V of cerebral cortex and in hippocampal CA1 region in 14‐week‐old CPE‐KO mice showed more dendritic complexity compared with wild type (WT) mice. There were more dendritic intersections and more branch points in CPE‐KO vs. WT neurons. Comparison of pyramidal cortical neurons in 6‐ vs. 14‐week‐old WT mice showed a decrease in dendritic arborization, reflecting the occurrence of normal dendritic pruning. However, this did not occur in CPE‐KO neurons. Furthermore, analysis of spine morphology demonstrated a significant increase in the number of D‐type spines regarded as nonfunctional in the cortical neurons of CPE‐KO animals. Our findings suggest that CPE is an important, novel player in mediating appropriate dendritic patterning and spine formation in CNS neurons. © 2009 Wiley‐Liss, Inc.     

Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington's disease transgenic mice

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion coding for an expanded polyglutamine tract in the huntingtin protein. Dendritic abnormalities occur in human HD patients and in several transgenic mouse models of the disease. In this study, we examine, for the first time, dendrite and spine pathology in the R6/1 mouse model of HD, which mimics neurodegeneration seen in human HD. Enriching the environment of HD transgenic mice delays the onset of symptoms, so we also examine the effects of enrichment on dendrite pathology. Golgi-impregnated tissue from symptomatic R6/1 HD mice reveals a decrease in dendritic spine density and dendritic spine length in striatal medium spiny neurons and cortical pyramidal neurons. HD also causes a specific reduction in the proportion of bifurcated dendritic spines on basal dendrites of cortical pyramidal neurons. No differences in soma size, recurving distal dendrites, or dendritic branching were observed. Although home-cage environmental enrichment from 1 to 8 months of age increases spine density in wild-type mice, it has no effect on the spine pathology in HD mice. These results show that dendritic spine pathology in R6/1 HD mice resembles degenerative changes seen in human HD and in other transgenic mouse models of the disease. We thus provide further evidence that the HD mutation disrupts the connectivity in both neostriatum and cerebral cortex, which will contribute to motor and cognitive disease symptoms. Furthermore, we demonstrate that Huntington's disease pathology interferes with the normal plastic response of dendritic spines to environmental enrichment.     

The chronic administration of cerebrolysin induces plastic changes in the prefrontal cortex and dentate gyrus in aged mice

Cerebrolysin (Cbl) is a mixture of neuropeptides with effects similar to the endogenous neurotrophic factors and is considered one of the best drugs used in the treatment of dementias such as Alzheimer's disease (AD). In brains with AD, morphological changes in the dendrites of pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of this drug on the dendrites of pyramidal neurons of the PFC and CA1 dorsal hippocampus and granule cells from the dentate gyrus (DG) and medium spiny neurons of the nucleus accumbens (NAcc) of aged mice. Cbl (5 ml kg(-1) , i.p.) was administered daily for 60 days to 6-month-old mice. Dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at 8 months ages. In all Cbl-treated mice a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC and granule cells of the DG was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC whereas in granule neurons of the DG the increase in dendritic length was further from the soma. Our results suggest that Cbl induces plastic modifications of dendritic morphology in the PFC and DG. These changes may explain the therapeutic effect seen in AD patients treated with Cbl.     

Neuronal plasticity and dendritic spines: effect of environmental enrichment on intact and postischemic rat brain.

The authors compared the influence of environmental enrichment on intact and lesioned brain, and tested the hypothesis that postischemic exposure to an enriched environment can alter dendritic spine density in pyramidal neurons contralateral to a cortical infarct. The middle cerebral artery was occluded distal to the striatal branches in spontaneously hypertensive rats postoperatively housed either in a standard or in an enriched environment. Intact rats were housed in the same environment. Three weeks later the brains were perfused in situ. The dendritic and spine morphology was studied with three-dimensional confocal laser scanning microscopy after microinjection of Lucifer yellow in pyramidal neurons in layers II/III and V/VI in the somatosensory cortex. In intact rats, the number of dendritic spines was significantly higher in the enriched group than in the standard group in all layers ( P < 0.05). Contralateral to the infarct, pyramidal neurons in layers II/III, which have extensive intracortical connections that may play a role in cortical plasticity, had significantly more spines in the enriched group than in the standard group ( P < 0.05). No difference was observed in layers V/VI. They conclude that housing rats in an enriched environment significantly increases spine density in superficial cortical layers in intact and lesioned brain, but in deeper layers of intact brain.     

Spiny stellates as cells of origin of association fibres from area 17 to area 18 in the cat''s neocortex

Neurons in the cat's area 17 were stained in Golgi-like fashion following injection of horseradish peroxidase into area 18. Such staining allows classification of neurons on the basis of dendritic morphology. The types of neurons found in area 17 are: pyramidal cells in layers 2,3 and 4ab; spiny stellate cells in the lower part of layer 3, and in layer 4ab; and a few pyramidal and spindle cells in layer 5. The axons of the spiny stellate cells are finer than those of pyramidal cells; they give off collatera;s in deeper cortical layers and may bifurcate when entering the white matter. Spiny stellates in area 17 do not project to area 19; after injections are made into area 17, these neurons are found neither in area 18 nor in area 19. The spiny stellate cell with a long axonis thus categorized as a projection neuron which takes part in the pathway from area 17 to ipsilateral and contralateral¹⁰ area 18.     

A Golgi study of the principal projection neurons of the medial cortex of the lizard Podarcis hispanica

The medial cortex of lizards is a simple three-layered brain region displaying many characteristics that parallel the hippocampal fascia dentata of mammals. Its principal neurons form a morphologically diverse population, partly as a result of the prominent continuous growth of this nervous center. By using the classic Golgi impregnation method, we describe here the morphology of the principal neurons populating the medial cortex of Podarcis hispanica. These were projection neurons giving off descending axons. These axons displayed deep collateral branches provided with prominent axonal boutons, while the main axonal branch reached adjacent cortical areas and the bilateral septum. According to three main classification criteria, dendritic tree pattern, dendritic spine covering, and soma size, we have distinguished eight different types of projection neurons. Five of them, “heavily spiny granular” (monotufted, medium-sized), “heavily spiny bitufted” (large), “spiny bitufted” (medium-sized), “sparsely spiny bitufted” (small), and “superficial multipolar” (small), were found in the cell layer, whereas the three others lay outside this layer and were regarded as ectopic types (“outer plexiform ectopic bitufted,” “inner plexiform ectopic bitufted”, and “inner plexiform monotufted”). Additional secondary criteria, soma position and shape, allowed us to further classify bitufted neurons into three distinct subtypes each: “superficial-round,” “intermediate-fusiform,” and “deep-pyramidal.” Moreover, a variety of small impregnated cells were observed; they probably represented newly generated immature neurons that had not yet completed their development. These cell types were compared with those reported previously in Golgi, immunocytochemical, and electron-microscopy studies, both in the reptilian medial cortex and in the mammalian dentate area. Presumably age-related changes and synaptic relationships of these projection cells in the medial cortex circuitry were analyzed. J. Comp. Neurol. 385:528–564, 1997. © 1997 Wiley-Liss, Inc.     

Kalirin loss results in cortical morphological alterations

Morphogenesis of pyramidal neuronal dendrites and spines is crucial for the formation and refinement of forebrain neuronal circuits underlying cognition. Aberrant dendrite and spine morphology is associated with neuropathological disorders. However, the molecular mechanisms controlling pyramidal neuronal dendrite and spine morphogenesis in vivo remain largely unknown. Kalirin is a brain-specific guanine-nucleotide exchange factor for Rho-like small GTPases, and an important regulator of spine morphogenesis in cultured neurons. Here we show that RNAi-dependent knockdown of kalirin in cultured neurons affected dendrite morphology. Cortical pyramidal neurons from KALRN-null mice showed reduced spine density and impaired activity-dependent spine plasticity; and they exhibited reduced complexity of dendritic trees. KALRN-null mice also displayed smaller neuronal cell bodies and reductions in the size of the cortex and cortical layers. These data demonstrate important roles for kalirin in the regulation of cortical structure, ultrastructure, and spine structural plasticity.     

Dendritic morphology of neurons in medial prefrontal cortex,hippocampus, and nucleus accumbens in adult SH rats

We have studied, in spontaneously hypertensive (SH) rats at different ages (2, 4, and 8 months old), the dendritic morphological changes of the pyramidal neurons of the medial prefrontal cortex (mPFC) and hippocampus and medium spiny neurons of the nucleus accumbens (NAcc) induced by the chronic effect of high‐blood pressure. As control animals, we used Wistar‐Kioto (WK) rats. Blood pressure was measured every 2 months to confirm the increase in arterial blood pressure. Spontaneous locomotor activity was assessed, and then brains were removed to study the dendritic morphology by the Golgi‐Cox stain method followed by Sholl analysis. SH animals at 4 and 8 months of age showed decreased spine density in pyramidal neurons from the mPFC and in medium spiny cells from the NAcc. At 8 months of age as well the pyramidal neurons from the hippocampus exhibited a reduction in the number of dendritic spines. An increase in locomotion in a novel environment at all ages in the SH rats was observed. Our results indicate that high‐blood pressure alters the neuronal dendrite morphology of the mPFC, hippocampus, and NAcc. The increased locomotion behavior supports the idea that dopaminergic transmission is altered in the SH rats. This could enhance our understanding of the consequences of chronic high‐blood pressure on brain structure, which may implicate cognitive impairment in hypertensive patients. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

The NMDA receptor co-agonists, D-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex

There is substantial evidence, both pharmacological and genetic, that hypofunction of the N-methyl-d-aspartate receptor (NMDAR) is a core pathophysiological feature of schizophrenia. There are morphological brain changes associated with schizophrenia, including perturbations in the dendritic morphology of cortical pyramidal neurons and reduction in cortical volume. Our experiments investigated whether these changes in dendritic morphology could be recapitulated in a genetic model of NMDAR hypofunction, the serine racemase knockout (SR-/-) mouse. Pyramidal neurons in primary somatosensory cortex (S1) of SR-/- mice had reductions in the complexity, total length, and spine density of apical and basal dendrites. In accordance with reduced cortical neuropil, SR-/- mice also had reduced cortical volume as compared to wild type mice. Analysis of S1 mRNA by DNA microarray and gene expression analysis revealed gene changes in SR-/- that are associated with psychiatric and neurologic disorders, as well as neurodevelopment. The microarray analysis also identified reduced expression of brain derived neurotrophic factor (BDNF) in SR-/- mice. Follow-up analysis by ELISA confirmed a reduction of BDNF protein levels in the S1 of SR-/- mice. Finally, S1 pyramidal neurons in glycine transporter heterozygote (GlyT1+/-) mutants, which display enhanced NMDAR function, had increased dendritic spine density. These results suggest that proper NMDAR function is important for the arborization and spine density of pyramidal neurons in cortex. Moreover, they suggest that NMDAR hypofunction might, in part, be contributing to the dendritic and synaptic changes observed in schizophrenia and highlight this signaling pathway as a potential target for therapeutic intervention.     

Serotonin transporter knockout and repeated social defeat stress: impact on neuronal morphology and plasticity in limbic brain areas

Low expression of the human serotonin transporter (5-HTT) gene presumably interacts with stressful life events enhancing susceptibility for affective disorders. 5-Htt knockout (KO) mice display an anxious phenotype, and behavioural differences compared to wild-type (WT) mice are exacerbated after repeated loser experience in a resident-intruder stress paradigm. To assess whether genotype-dependent and stress-induced behavioural differences are reflected in alterations of neuronal morphology in limbic areas, we studied dendritic length and complexity of pyramidal neurons in the anterior cingulate and infralimbic cortices (CG, IL), hippocampus CA1 region, and of pyramidal neurons and interneurons in the lateral (La) and basolateral (BL) amygdaloid nuclei in Golgi-Cox-stained brains of male WT and 5-Htt KO control and loser mice. Spine density was analysed for IL apical and amygdaloid apical and basal pyramidal neuron dendrites. While group differences were absent for parameters analysed in CG, CA1 and amygdaloid interneurons, pyramidal neurons in the IL displayed tendencies to shorter and less spinous distal apical dendrites in 5-Htt KO controls, and to extended proximal dendrites in WT losers compared to WT controls. In contrast, spine density of several dendritic compartments of amygdaloid pyramids was significantly higher in 5-Htt KO mice compared to WT controls. While a tendency to increased spine density was observed in the same dendritic compartments in WT after stress, changes were lacking in stressed compared to control 5-Htt KO mice. Our findings indicate that disturbed 5-HT homeostasis results in alterations of limbic neuronal morphology, especially in higher spinogenesis in amygdaloid pyramidal neurons. Social stress leads to similar but less pronounced changes in the WT, and neuroplasticity upon stress is reduced in 5-Htt KO mice.