Jelena Krmpotić-Nemanić (1921–2008): Contributions to Human Neuroanatomy

Jelena Krmpoti}-Nemani} (1921–2008) was a world-famous anatomist, internationally distinguished otolaryngologist, a member of the Croatian Academy of Sciences & Arts and appreciated professor at the School of Medicine University of Zagreb. The founding influence in her scientific career came from her mentor Drago Perovi} who was a student of Ferdinand Hochstetter, the leading authority in the field of human developmental neuroanatomy and embryology. Such an influence was obviously important in early shaping of the research agenda of Jelena Krmpoti}-Nemani}, and it remains important in a long series of studies on developing human telencephalon initiated by Ivica Kostovi} and his collaborators – with an always present and active support of Jelena Krmpoti}-Nemani}. The aim of this mini review is to briefly describe her numerous contributions to the anatomy of the human peripheral and central nervous system

Primate-Specific Origins and Migration of Cortical GABAergic Neurons

Gamma-aminobutyric-acidergic (GABAergic) cells form a very heterogeneous population of neurons that play a crucial role in the coordination and integration of cortical functions. Their number and diversity increase through mammalian brain evolution. Does evolution use the same or different developmental rules to provide the increased population of cortical GABAergic neurons? In rodents, these neurons are not generated in the pallial proliferative zones as glutamatergic principal neurons. They are produced almost exclusively by the subpallial proliferative zones, the ganglionic eminence (GE) and migrate tangentially to reach their target cortical layers. The GE is organized in molecularly different subdomains that produce different subpopulations of cortical GABAergic neurons. In humans and non-human primates, in addition to the GE, cortical GABAergic neurons are also abundantly generated by the proliferative zones of the dorsal telencephalon. Neurogenesis in ventral and dorsal telencephalon occurs with distinct temporal profiles. These dorsal and ventral lineages give rise to different populations of GABAergic neurons. Early-generated GABAergic neurons originate from the GE and mostly migrate to the marginal zone and the subplate. Later-generated GABAergic neurons, originating from both proliferative sites, populate the cortical plate. Interestingly, the pool of GABAergic progenitors in dorsal telencephalon produces mainly calretinin neurons, a population known to be significantly increased and to display specific features in primates. We conclude that the development of cortical GABAergic neurons have exclusive features in primates that need to be considered in order to understand pathological mechanisms leading to some neurological and psychiatric diseases

Quantitative Analysis of Basal Dendritic Tree of Layer IIIc Pyramidal Neurons in Different Areas of Adult Human Frontal Cortex

Large long projecting (cortico-cortical) layer IIIc pyramidal neurons were recently disclosed to be in the basis of cognitive processing in primates. Therefore, we quantitatively examined the basal dendritic morphology of these neurons by using rapid Golgi and Golgi Cox impregnation methods among three distinct Brodmann areas (BA) of an adult human frontal cortex: the primary motor BA4 and the associative magnopyramidal BA9 from left hemisphere and the Broca’s speech BA45 from both hemispheres. There was no statistically significant difference in basal dendritic length or complexity, as dendritic spine number or their density between analyzed BA’s. In addition, we analyzed each of these BA’s immunocytochemically for distribution of SMI-32, a marker of largest long distance projecting neurons. Within layer IIIc, the highest density of SMI-32 immunopositive pyramidal neurons was observed in associative BA9, while in primary BA4 they were sparse. Taken together, these data suggest that an increase in the complexity of cortico-cortical network within human frontal areas of different functional order may be principally based on the increase in density of large, SMI-32 immunopositive layer IIIc neurons, rather than by further increase in complexity of their dendritic tree and synaptic network

Distinct Origin of GABA-ergic Neurons in Forebrain of Man, Nonhuman Primates and Lower Mammals

In this mini-review we present recent data about origin of GABA-ergic (gama-aminobutyric acid) neurons in the mammalian forebrain, including the diencephalon and telencephalon. The interest in GABA-ergic neurons, which in cerebral cortex mostly correspond to local circuit neurons (interneurons), has increased in the past decade. Many studies have shown that in lower mammals all hippocampal and almost all neo-cortical GABA-ergic neurons are born in the specific region named ganglionic eminence, and not locally in proliferative layers all around telencephalic vesicle. The ganglionic eminence, that represents a region with thick proliferative-subventricular layer in the ventral (basal) part of telencephalon, was classically thought to give neurons to basal ganglia and septal nuclei, whereas proliferative layers of dorsal telencephalon give neurons to cerebral cortex including hippocampus. It was thought that neurons migrate from proliferative layer to their target region following a radial orientation. However, data in lower mammals showed that this is the case only for glutamatergic principal cells, i.e. projection neurons. GABA-ergic neurons use long distance tangentional migration, parallel to pial surface to reach, from ganglionic eminence, their targeting layer in the cerebral cortex. Especially intriguing, but frequently neglecting, several studies suggest that mammalian evolution might use different developmental rules to provide GABA-ergic neurons to an expending brain. In this review we focus on specific events underlying GABA-ergic neuron development in human and non-human primates. Disturbances of the GABAergic network are found in many neurological and psychiatric disorders, some of them might result from altered production or migration of these neurons during development. Therefore, it is crucial to understand human-specific mechanisms that regulate the development of GABA-ergic neurons

Axon morphology of rapid Golgistained pyramidal neurons in the prefrontal cortex in schizophrenia

Aim To analyze axon morphology on rapid Golgi impregnated pyramidal neurons in the dorsolateral prefrontal cortex in schizophrenia. Methods Postmortem brain tissue from five subjects diagnosed with schizophrenia and five control subjects without neuropathological findings was processed with the rapid Golgi method. Layer III and layer V pyramidal neurons from Brodmann area 9 were chosen in each brain for reconstruction with Neurolucida software. The axons and cell bodies of 136 neurons from subjects with schizophrenia and of 165 neurons from control subjects were traced. The data obtained by quantitative analysis were compared between the schizophrenia and control group with the t test. Results Axon impregnation length was consistently greater in the schizophrenia group. The axon main trunk length was significantly greater in the schizophrenia than in the control group (93.7±36.6 μm vs 49.8±9.9 μm, P=0.032). Furthermore, in the schizophrenia group more axons had visibly stained collaterals (14.7% vs 5.5%). Conclusion Axon rapid Golgi impregnation stops at the beginning of the myelin sheath. The increased axonal staining in the schizophrenia group could, therefore, be explained by reduced axon myelination. Such a decrease in axon myelination is in line with both the disconnection hypothesis and the two-hit model of schizophrenia as a neurodevelopmental disease. Our results support that the cortical circuitry disorganization in schizophrenia might be caused by functional alterations of two major classes of principal neurons due to altered oligodendrocyte development

Quantitative Analysis of Basal Dendritic Tree of Layer IIIc Pyramidal Neurons in Different Areas of Adult Human Frontal Cortex

Large long projecting (cortico-cortical) layer IIIc pyramidal neurons were recently disclosed to be in the basis of cognitive processing in primates. Therefore, we quantitatively examined the basal dendritic morphology of these neurons by using rapid Golgi and Golgi Cox impregnation methods among three distinct Brodmann areas (BA) of an adult human frontal cortex: the primary motor BA4 and the associative magnopyramidal BA9 from left hemisphere and the Broca’s speech BA45 from both hemispheres. There was no statistically significant difference in basal dendritic length or complexity, as dendritic spine number or their density between analyzed BA’s. In addition, we analyzed each of these BA’s immunocytochemically for distribution of SMI-32, a marker of largest long distance projecting neurons. Within layer IIIc, the highest density of SMI-32 immunopositive pyramidal neurons was observed in associative BA9, while in primary BA4 they were sparse. Taken together, these data suggest that an increase in the complexity of cortico-cortical network within human frontal areas of different functional order may be principally based on the increase in density of large, SMI-32 immunopositive layer IIIc neurons, rather than by further increase in complexity of their dendritic tree and synaptic network

Anatomija orofacijalne inervacije

The whole human body receives rich sensory innervation with only one exception and that is the brain tissue. The orofacial region is hence no exception. The head region consequently receives a rich network of sensory nerves making it special because the two types of sensory fibres, visceral and somatic overlap, especially in the pharynx. Also, different pain syndromes that affect this region are rather specific in comparison to their presentation in other body regions. With this review article we wanted to show the detailed anatomy of the peripheral sensory pathways, because of its importance in everyday body functions (eating, drinking, speech) as well as the importance it has in pathological conditions (pain syndromes), in diagnostics and regional analgesia and anaesthesia.Osjetna živčana vlakna prožimaju gotovo sva tkiva osim mozga ne izuzimajući tako ni orofacijalnu regiju. Područje glave je izrazito dobro osjetno inervirano, no ova je regija također posebna jer kao posljedica razvojnih događaja dolazi do preklapanja visceralne i somatske inervacije osobito u području ždrijela. Također, bolni sindromi koji zahvaćaju orofacijalnu regiju pokazuju neke specifičnosti koje ne nalazimo u drugim dijelovima tijela. Ovim preglednim člankom htjeli smo prikazati detaljnu anatomiju perifernih osjetnih putova zbog njihove važnost u svakodnevnim funkcijama za koje je odgovorno ovo područje (jedenje, pijenje, govorenje), ali isto tako i važnosti koju ima u patološkim slučajevima (bolni sindromi) te u dijagnostici i regionalnoj analgeziji i anesteziji

Distinct Origin of GABA-ergic Neurons in Forebrain of Man, Nonhuman Primates and Lower Mammals

In this mini-review we present recent data about origin of GABA-ergic (gama-aminobutyric acid) neurons in the mammalian forebrain, including the diencephalon and telencephalon. The interest in GABA-ergic neurons, which in cerebral cortex mostly correspond to local circuit neurons (interneurons), has increased in the past decade. Many studies have shown that in lower mammals all hippocampal and almost all neo-cortical GABA-ergic neurons are born in the specific region named ganglionic eminence, and not locally in proliferative layers all around telencephalic vesicle. The ganglionic eminence, that represents a region with thick proliferative-subventricular layer in the ventral (basal) part of telencephalon, was classically thought to give neurons to basal ganglia and septal nuclei, whereas proliferative layers of dorsal telencephalon give neurons to cerebral cortex including hippocampus. It was thought that neurons migrate from proliferative layer to their target region following a radial orientation. However, data in lower mammals showed that this is the case only for glutamatergic principal cells, i.e. projection neurons. GABA-ergic neurons use long distance tangentional migration, parallel to pial surface to reach, from ganglionic eminence, their targeting layer in the cerebral cortex. Especially intriguing, but frequently neglecting, several studies suggest that mammalian evolution might use different developmental rules to provide GABA-ergic neurons to an expending brain. In this review we focus on specific events underlying GABA-ergic neuron development in human and non-human primates. Disturbances of the GABAergic network are found in many neurological and psychiatric disorders, some of them might result from altered production or migration of these neurons during development. Therefore, it is crucial to understand human-specific mechanisms that regulate the development of GABA-ergic neurons

Extraordinary neoteny of synaptic spines in the human prefrontal cortex

The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by two- to threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders

The protracted maturation of associative layer IIIC pyramidal neurons in the human prefrontal cortex during childhood: a major role in cognitive development and selective alteration in autism

The human specific cognitive shift starts around the age of 2 years with the onset of self-awareness, and continues with extraordinary increase in cognitive capacities during early childhood. Diffuse changes in functional connectivity in children aged 2-6 years indicate an increase in the capacity of cortical network. Interestingly, structural network complexity does not increase during this time and, thus, it is likely to be induced by selective maturation of a specific neuronal subclass. Here, we provide an overview of a subclass of cortico-cortical neurons, the associative layer IIIC pyramids of the human prefrontal cortex. Their local axonal collaterals are in control of the prefrontal cortico-cortical output, while their long projections modulate inter-areal processing. In this way, layer IIIC pyramids are the major integrative element of cortical processing, and changes in their connectivity patterns will affect global cortical functioning. Layer IIIC neurons have a unique pattern of dendritic maturation. In contrast to other classes of principal neurons, they undergo an additional phase of extensive dendritic growth during early childhood, and show characteristic molecular changes. Taken together, circuits associated with layer IIIC neurons have the most protracted period of developmental plasticity. This unique feature is advanced but also provides a window of opportunity for pathological events to disrupt normal formation of cognitive circuits involving layer IIIC neurons. In this manuscript, we discuss how disrupted dendritic and axonal maturation of layer IIIC neurons may lead into global cortical disconnectivity, affecting development of complex communication and social abilities. We also propose a model that developmentally dictated incorporation of layer IIIC neurons into maturing cortico-cortical circuits between 2 to 6 years will reveal a previous (perinatal) lesion affecting other classes of principal neurons. This "disclosure" of pre-existing functionally silent lesions of other neuronal classes induced by development of layer IIIC associative neurons, or their direct alteration, could be found in different forms of autism spectrum disorders. Understanding the gene-environment interaction in shaping cognitive microcircuitries may be fundamental for developing rehabilitation and prevention strategies in autism spectrum and other cognitive disorders