Fundamental or forgotten? Is Pierre Paul Broca still relevant in modern neuroscience?

The ability to speak is a unique human capacity, but where is it located in our brains? This question is closely connected to the pioneering work of Pierre Paul Broca in the 1860s. Based on post-mortem observations of aphasic patients' brains, Broca located language production in the 3rd convolution of the left frontal lobe and thus reinitiated the localizationist view of brain functions. However, contemporary neuroscience has partially rejected this view in favor of a network-based perspective. This leads to the question, whether Broca's findings are still relevant today. In this mini-review, we discuss current and historical implications of Broca's work by focusing on his original contribution and contrasting it with contemporary knowledge. Borrowing from Broca's famous quote, our review shows that humans indeed "speak with the left hemisphere"- but Broca's area is not the sole "seat of articulatory language".

Functional Connectivity Pattern of the Internal Hippocampal Network in Awake Pigeons: A Resting-State fMRI Study.

In the last two decades, the avian hippocampus has been repeatedly studied with respect to its architecture, neurochemistry, and connectivity pattern. We review these insights and conclude that we unfortunately still lack proper knowledge on the interaction between the different hippocampal subregions. To fill this gap, we need information on the functional connectivity pattern of the hippocampal network. These data could complement our structural connectivity knowledge. To this end, we conducted a resting-state fMRI experiment in awake pigeons in a 7-T MR scanner. A voxel-wise regression analysis of blood oxygenation level-dependent (BOLD) fluctuations was performed in 6 distinct areas, dorsomedial (DM), dorsolateral (DL), triangular shaped (Tr), dorsolateral corticoid (CDL), temporo-parieto-occipital (TPO), and lateral septum regions (SL), to establish a functional connectivity map of the avian hippocampal network. Our study reveals that the system of connectivities between CDL, DL, DM, and Tr is the functional backbone of the pigeon hippocampal system. Within this network, DM is the central hub and is strongly associated with DL and CDL BOLD signal fluctuations. DM is also the only hippocampal region to which large Tr areas are functionally connected. In contrast to published tracing data, TPO and SL are only weakly integrated in this network. In summary, our findings uncovered a structurally otherwise invisible architecture of the avian hippocampal formation by revealing the dynamic blueprints of this network.

Phylogenetic reduction of the magnocellular red nucleus in primates and inter-subject variability in humans.

Introduction: The red nucleus is part of the motor system controlling limb movements. While this seems to be a function common in many vertebrates, its organization and circuitry have undergone massive changes during evolution. In primates, it is sub-divided into the magnocellular and parvocellular parts that give rise to rubrospinal and rubro-olivary connection, respectively. These two subdivisions are subject to striking variation within the primates and the size of the magnocellular part is markedly reduced in bipedal primates including humans. The parvocellular part is part of the olivo-cerebellar circuitry that is prominent in humans. Despite the well-described differences between species in the literature, systematic comparative studies of the red nucleus remain rare. Methods: We therefore mapped the red nucleus in cytoarchitectonic sections of 20 primate species belonging to 5 primate groups including prosimians, new world monkeys, old world monkeys, non-human apes and humans. We used Ornstein-Uhlenbeck modelling, ancestral state estimation and phylogenetic analysis of covariance to scrutinize the phylogenetic relations of the red nucleus volume. Results: We created openly available high-resolution cytoarchitectonic delineations of the human red nucleus in the microscopic BigBrain model and human probabilistic maps that capture inter-subject variations in quantitative terms. Further, we compared the volume of the nucleus across primates and showed that the parvocellular subdivision scaled proportionally to the brain volume across the groups while the magnocellular part deviated significantly from the scaling in humans and non-human apes. These two groups showed the lowest size of the magnocellular red nucleus relative to the whole brain volume and the largest relative difference between the parvocellular and magnocellular subdivision. Discussion: That is, the red nucleus has transformed from a magnocellular-dominated to a parvocellular-dominated station. It is reasonable to assume that these changes are intertwined with evolutionary developments in other brain regions, in particular the motor system. We speculate that the interspecies variations might partly reflect the differences in hand dexterity but also the tentative involvement of the red nucleus in sensory and cognitive functions.

Neuronal circuits within the homing pigeon hippocampal formation.

The current study aimed to reveal in detail patterns of intrahippocampal connectivity in homing pigeons (Columba livia). In light of recent physiological evidence suggesting differences between dorsomedial and ventrolateral hippocampal regions and a hitherto unknown laminar organization along the transverse axis, we also aimed to gain a higher-resolution understanding of the proposed pathway segregation. Both in vivo and high-resolution in vitro tracing techniques were employed and revealed a complex connectivity pattern along the subdivisions of the avian hippocampus. We uncovered connectivity pathways along the transverse axis that started in the dorsolateral hippocampus and continued to the dorsomedial subdivision, from where information was relayed to the triangular region either directly or indirectly via the V-shaped layers. The often-reciprocal connectivity along these subdivisions displayed an intriguing topographical arrangement such that two parallel pathways could be discerned along the ventrolateral (deep) and dorsomedial (superficial) aspects of the avian hippocampus. The segregation along the transverse axis was further supported by expression patterns of the glial fibrillary acidic protein and calbindin. Moreover, we found strong expression of Ca2+ /calmodulin-dependent kinase IIα and doublecortin in the lateral but not medial V-shape layer, indicating a difference between the two V-shaped layers. Overall, our findings provide an unprecedented, detailed description of avian intrahippocampal pathway connectivity, and confirm the recently proposed segregation of the avian hippocampus along the transverse axis. We also provide further support for the hypothesized homology of the lateral V-shape layer and the dorsomedial hippocampus with the dentate gyrus and Ammon's horn of mammals, respectively.

The Intriguing Contribution of Hippocampal Long-Term Depression to Spatial Learning and Long-Term Memory.

Long-term potentiation (LTP) and long-term depression (LTD) comprise the principal cellular mechanisms that fulfill established criteria for the physiological correlates of learning and memory. Traditionally LTP, that increases synaptic weights, has been ascribed a prominent role in learning and memory whereas LTD, that decreases them, has often been relegated to the category of "counterpart to LTP" that serves to prevent saturation of synapses. In contradiction of these assumptions, studies over the last several years have provided functional evidence for distinct roles of LTD in specific aspects of hippocampus-dependent associative learning and information encoding. Furthermore, evidence of the experience-dependent "pruning" of excitatory synapses, the majority of which are located on dendritic spines, by means of LTD has been provided. In addition, reports exist of the temporal and physical restriction of LTP in dendritic compartments by means of LTD. Here, we discuss the role of LTD and LTP in experience-dependent information encoding based on empirical evidence derived from conjoint behavioral and electrophysiological studies conducted in behaving rodents. We pinpoint the close interrelation between structural modifications of dendritic spines and the occurrence of LTP and LTD. We report on findings that support that whereas LTP serves to acquire the general scheme of a spatial representation, LTD enables retention of content details. We argue that LTD contributes to learning by engaging in a functional interplay with LTP, rather than serving as its simple counterpart, or negator. We propose that similar spatial experiences that share elements of neuronal representations can be modified by means of LTD to enable pattern separation. Therewith, LTD plays a crucial role in the disambiguation of similar spatial representations and the prevention of generalization.

Mechanistic flexibility of the retrosplenial cortex enables its contribution to spatial cognition.

The retrosplenial cortex (RC) is a brain structure crucial for spatial navigation and memory. It contains neurons such as head direction cells, border cells, as well as other cells supporting spatial and contextual encoding. How such complex and diverse neuronal properties are generated by RC microcircuitry and how they jointly orchestrate subsequent behavior remains enigmatic. Here, we consider recent findings that extend current knowledge about how the RC modulates spatial navigation and spatial cognition. We argue that the integrative properties of RC allow the combination of idiothetic cues, spatial relations (allocentric and egocentric), and environmental features (landmarks, boundaries, etc.) into a spatial map that can dynamically support goal-directed navigation. Furthermore, the mnemonic functions of RC suggest its possible role in autobiographical information storage.

Strain-dependent regulation of hippocampal long-term potentiation by dopamine D1/D5 receptors in mice.

The magnitude and persistency of long-term potentiation (LTP) in the rodent hippocampus is species-dependent: rats express more robust and more prolonged LTP in response to a broader afferent frequency range than mice. The C57Bl/6 mouse is an extremely popular murine strain used in studies of hippocampal synaptic plasticity and spatial learning. Recently it was reported that it expresses impoverished LTP compared to other murine strains. Given the important role of the dopamine D1/D5 receptor (D1/D5R) in the maintenance of LTP and in memory consolidation, we explored to what extent strain-dependent differences in LTP in mice are determined by differences in D1/D5R-control. In CaOlaHsd mice, robust LTP was induced that lasted for over 24 h and which was significantly greater in magnitude than LTP induced in C57Bl/6 mice. Intracerebral treatment with a D1/D5R-antagonist (SCH23390) prevented both the early and late phase of LTP in CaOlaHsd mice, whereas only late-LTP was impaired in C57Bl/6 mice. Treatment with a D1/D5R-agonist (Chloro-PB) facilitated short-term potentiation (STP) into LTP (> 24 h) in both strains, whereby effects became evident earlier in CaOlaHsd compared to C57Bl/6 mice. Immunohistochemical analysis revealed a significantly higher expression of D1-receptors in the stratum lacunosum moleculare of CaOlaHsd compared to C57Bl/6 mice. These findings highlight differences in D1/D5R- dependent regulation of strain-dependent variations in hippocampal LTP in C57Bl/6 and CaOlaHsd mice, that may be mediated, in part, by differences in the expression of D1R in the hippocampus.

A cortex-like canonical circuit in the avian forebrain.

Although the avian pallium seems to lack an organization akin to that of the cerebral cortex, birds exhibit extraordinary cognitive skills that are comparable to those of mammals. We analyzed the fiber architecture of the avian pallium with three-dimensional polarized light imaging and subsequently reconstructed local and associative pallial circuits with tracing techniques. We discovered an iteratively repeated, column-like neuronal circuitry across the layer-like nuclear boundaries of the hyperpallium and the sensory dorsal ventricular ridge. These circuits are connected to neighboring columns and, via tangential layer-like connections, to higher associative and motor areas. Our findings indicate that this avian canonical circuitry is similar to its mammalian counterpart and might constitute the structural basis of neuronal computation.

Functional organization of telencephalic visual association fields in pigeons.

Birds show remarkable visual abilities that surpass most of our visual psychophysiological abilities. In this study, we investigated visual associative areas of the tectofugal visual system in pigeons. Similar to the condition in mammals, ascending visual pathways in birds are subdivided into parallel form/color vs. motion streams at the thalamic and primary telencephalic level. However, we know practically nothing about the functional organization of those telencephalic areas that receive input from the primary visual telencephalic fields. The current study therefore had two objectives: first, to reveal whether these visual associative areas of the tectofugal system are activated during visual discrimination tasks; second, to test whether separated form/color vs. motion pathways can be discerned among these association fields. To this end, we trained pigeons to discriminate either form/color or motion stimuli and used the immediate early gene protein ZENK to capture the activity of the visual associative areas during the task. We could indeed identify several visual associative telencephalic structures by activity pattern changes during discriminations. However, none of these areas displayed a difference between form/color vs. motion sessions. The presence of such a distinction in thalamo-telencephalic, but not in further downstream visual association areas opens the possibility that these separate streams converge very early in birds, which possibly minimizes long-range connections due to the evolutionary pressure toward miniaturized brains.

A GABAergic tecto-tegmento-tectal pathway in pigeons.

Previous studies have demonstrated that the optic tecta of the left and right brain halves reciprocally inhibit each other in birds. In mammals, the superior colliculus receives inhibitory γ-aminobutyric acid (GABA)ergic input from the basal ganglia via both the ipsilateral and the contralateral substantia nigra pars reticulata (SNr). This contralateral SNr projection is important in intertectal inhibition. Because the basal ganglia are evolutionarily conserved, the tectal projections of the SNr may show a similar pattern in birds. Therefore, the SNr could be a relay station in an indirect tecto-tectal pathway constituting the neuronal substrate for the tecto-tectal inhibition. To test this hypothesis, we performed bilateral anterograde and retrograde tectal tracing combined with GABA immunohistochemistry in pigeons. Suprisingly, the SNr has only ipsilateral projections to the optic tectum, and these are non-GABAergic. Inhibitory GABAergic input to the contralateral optic tectum arises instead from a nearby tegmental region that receives input from the ipsilateral optic tectum. Thus, a disynaptic pathway exists that possibly constitutes the anatomical substrate for the inhibitory tecto-tectal interaction. This pathway likely plays an important role in attentional switches between the laterally placed eyes of birds. J. Comp. Neurol. 524:2886-2913, 2016. © 2016 Wiley Periodicals, Inc.

A three-dimensional digital atlas of the starling brain.

Because of their sophisticated vocal behaviour, their social nature, their high plasticity and their robustness, starlings have become an important model species that is widely used in studies of neuroethology of song production and perception. Since magnetic resonance imaging (MRI) represents an increasingly relevant tool for comparative neuroscience, a 3D MRI-based atlas of the starling brain becomes essential. Using multiple imaging protocols we delineated several sensory systems as well as the song control system. This starling brain atlas can easily be used to determine the stereotactic location of identified neural structures at any angle of the head. Additionally, the atlas is useful to find the optimal angle of sectioning for slice experiments, stereotactic injections and electrophysiological recordings. The starling brain atlas is freely available for the scientific community.