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Comparison of chicken and mouse medial pallial subdivisions. Schematic drawings of frontal sections through the telencephalon of a chicken (at E16) and a mouse (at E18.5), at rostral intermediate, or caudal levels, showing the major subdivisions of the medial pallium. A color code is used to compare these subdivisions between species. In these schemes, dorsal is to the top and medial is to the left. In the chicken, the rostralmost part is represented by the APHr. The asterisk points to an ectopic part of chicken APHr (possibly a group tangentially migrated cells), observed at the surface of APHm at intermediate and caudal levels of the medial pallium. The rostralmost part of mouse is not represented here, but appears to include the indusium griseum. For abbreviations see list. See text for more details.
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We carried out a study of the expression patterns of seven developmental regulatory genes (Lef1, Lhx2, Lhx9, Lhx5, Lmo3, Lmo4, and Prox1), in combination with topological position, to identify the medial pallial derivatives, define its major subdivisions, and compare them between mouse and chicken. In both species, the medial pallium is defined as...
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... Fortunately, the resulting hHOs maintained their spherical structures without loose ChP tissues throughout the growth period (Fig. 3b). Key biomarkers of the development process are summarized in Fig. 3c [38][39][40] . The expression of FOXG1, LEF1, and PAX6 in day-30 hHOs indicated successful induction into the DMT stage (Fig. 3d). ...
Human hippocampal organoids (hHOs) derived from human induced pluripotent stem cells (hiPSCs) have emerged as promising models for investigating neurodegenerative disorders, such as schizophrenia and Alzheimer’s disease. However, obtaining the electrical information of these free-floating organoids in a noninvasive manner remains a challenge using commercial multi-electrode arrays (MEAs). The three-dimensional (3D) MEAs developed recently acquired only a few neural signals due to limited channel numbers. Here, we report a hippocampal cyborg organoid (cyb-organoid) platform coupling a liquid metal-polymer conductor (MPC)-based mesh neuro-interface with hHOs. The mesh MPC (mMPC) integrates 128-channel multielectrode arrays distributed on a small surface area (~2*2 mm). Stretchability (up to 500%) and flexibility of the mMPC enable its attachment to hHOs. Furthermore, we show that under Wnt3a and SHH activator induction, hHOs produce HOPX⁺ and PAX6⁺ progenitors and ZBTB20⁺PROX1⁺ dentate gyrus (DG) granule neurons. The transcriptomic signatures of hHOs reveal high similarity to the developing human hippocampus. We successfully detect neural activities from hHOs via the mMPC from this cyb-organoid. Compared with traditional planar devices, our non-invasive coupling offers an adaptor for recording neural signals from 3D models.
... The insular cortex and the lateral entorhinal cortex are known to originate from the lateral pallium. The ventral portion at the pallial-subpallial boundary gives rise to the amygdala [26][27][28]. In contrast, lateral, medial, and caudal ganglionic eminences (LGE, MGE, and CGE) in the subpallium develop as the basal ganglia [29]. ...
... Wnts are expressed at the dorsal midline of the telencephalon, known as the cortical hem. Wnt signaling is important for patterning the medial pallium, which later develops into the hippocampus and medial entorhinal cortex [26,31]. When Wnt3a is knocked out and Wnt signaling is lost, the mouse hippocampus does not develop normally [32,33]. ...
... In addition, organoids representing specific telencephalic regions other than the cortex have been reported based on the combined use of patterning molecules such as BMP4, Wnt, and Shh. The cortical hem plays an important role in the development of dorsomedial telencephalic tissues such as the hippocampus, choroid plexus, and entorhinal cortex by providing Wnt and BMP [26,31,76]. In 2014, the Sasai group generated floating EB-like aggregates (SFEBq) resembling the hippocampus and choroid plexus using BMP4 and the Wnt activator CHIR99021. ...
The telencephalon is the largest region of the brain and processes critical brain activity. Despite much progress, our understanding of the telencephalon’s function, development, and pathophysiological processes remains largely incomplete. Recently, 3-dimensional brain models, known as brain organoids, have attracted considerable attention in modern neurobiological research. Brain organoids have been proven to be valuable for studying the neurodevelopmental principles and pathophysiology of the brain, as well as for developing potential therapeutics. Brain organoids can change the paradigm of current research, replacing animal models. However, there are still limitations, and efforts are needed to improve brain organoid models. In this review, we provide an overview of the development and function of the telencephalon, as well as the techniques and scientific methods used to create fully developed telencephalon organoids. Additionally, we explore the limitations and challenges of current brain organoids and potential future advancements.
... Furthermore, the mossy fiber-like structures seen in the mammalian DG have not been found in avian HF (Faber et al., 1989;Montagnese et al., 1993Montagnese et al., , 1996Tombol et al., 2000;Herold et al., 2014). To date, several subdivisions have been proposed for avian HFs, using several methods and criteria, such as histology, immunohistochemistry, projection relationships, and developmental origin (Kuenzel and Masson, 1988;Wild, 2004, 2006;Suarez et al., 2006;Gupta et al., 2012;Abellan et al., 2014;Herold et al., 2014;Atoji et al., 2016;Medina et al., 2017a;Puelles et al., 2018). However, there is controversy over homologous regions within avian HFs for mammalian DG and CA fields, and it is difficult to say that a one-to-one correspondence between avian HFs and mammalian HFs have been established for subdivision within HFs Wild, 2004, 2006;Kempermann, 2012;Abellan et al., 2014;Herold et al., 2014;Atoji et al., 2016;Hevner, 2016;Striedter, 2016;Medina et al., 2017a). ...
... To date, several subdivisions have been proposed for avian HFs, using several methods and criteria, such as histology, immunohistochemistry, projection relationships, and developmental origin (Kuenzel and Masson, 1988;Wild, 2004, 2006;Suarez et al., 2006;Gupta et al., 2012;Abellan et al., 2014;Herold et al., 2014;Atoji et al., 2016;Medina et al., 2017a;Puelles et al., 2018). However, there is controversy over homologous regions within avian HFs for mammalian DG and CA fields, and it is difficult to say that a one-to-one correspondence between avian HFs and mammalian HFs have been established for subdivision within HFs Wild, 2004, 2006;Kempermann, 2012;Abellan et al., 2014;Herold et al., 2014;Atoji et al., 2016;Hevner, 2016;Striedter, 2016;Medina et al., 2017a). Briefly, there are three possibilities for homology with subdivisions of mammalian HFs for the subdivision of avian HFs. ...
... Some neuronal markers, such as calbindin, CaMKII, and DCX, which are used from a neurochemical point of view and in immunohistochemistry, are also used in the avian HF (Suarez et al., 2006;Melleu et al., 2013;Herold et al., 2019;Rook et al., 2023). A particularly interesting study using HF cell type markers by Atoji et al. (2016) showed that the orthologue of the DG granule cell population marker, prox1, was not only available as a developmental chicken DG region marker (Gupta et al., 2012;Abellan et al., 2014), but was also expressed in adult pigeon V. Since the avian V has been proposed to be equivalent to the mammalian DG (Atoji and Wild, 2004;Suarez et al., 2006;Gupta et al., 2012;Herold et al., 2014;Atoji et al., 2016;Puelles et al., 2018), this raised the possibility that PROX1 could also be used as a marker for corresponding cells in the DG granule cell population marker in adult birds. To better understand the characteristics of serotonin-regulated neural circuits in the avian HF, it is necessary to increase the available markers for cell types within the avian HF. ...
Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically conserved neurotransmitter and modulator. Neurons utilizing serotonin have been identified in the central nervous systems of all vertebrates. In the central serotonergic system of vertebrate species examined so far, serotonergic neurons have been confirmed to exist in clusters in the brainstem. Although many serotonin-regulated cognitive, behavioral, and emotional functions have been elucidated in mammals, equivalents remain poorly understood in non-mammalian vertebrates. The purpose of this review is to summarize current knowledge of the anatomical organization and molecular features of the avian central serotonergic system. In addition, selected key functions of serotonin are briefly reviewed. Gene association studies between serotonergic system related genes and behaviors in birds have elucidated that the serotonergic system is involved in the regulation of behavior in birds similar to that observed in mammals. The widespread distribution of serotonergic modulation in the central nervous system and the evolutionary conservation of the serotonergic system provide a strong foundation for understanding and comparing the evolutionary continuity of neural circuits controlling corresponding brain functions within vertebrates. The main focus of this review is the chicken brain, with this type of poultry used as a model bird. The chicken is widely used not only as a model for answering questions in developmental biology and as a model for agriculturally useful breeding, but also in research relating to cognitive, behavioral, and emotional processes. In addition to a wealth of prior research on the projection relationships of avian brain regions, detailed subdivision similarities between avian and mammalian brains have recently been identified. Therefore, identifying the neural circuits modulated by the serotonergic system in avian brains may provide an interesting opportunity for detailed comparative studies of the function of serotonergic systems in mammals.
... For the identification of forebrain cell masses, we primarily followed the proposal of the Avian Brain Nomenclature Forum (Reiner et al., 2004) and the chick brain atlas (Puelles et al., 2019). For the developing chicken brain, we followed Puelles et al. (2000) as well as our own publications on the subject Abellán et al., , 2010Abellán et al., , 2014Medina et al., 2019), including those in which we identified new subdivisions of the central extended amygdala in developing chicken (Vicario et al., 2014; see also Pross et al., 2022), as well as a new telencephalic subdivision near the frontier with the hypothalamus, related to the subpreoptic region (SuPO) and a ventral part of the medial extended amygdala . ...
Understanding the neural mechanisms that regulate the stress response is critical to know how animals adapt to a changing world and is one of the key factors to be considered for improving animal welfare. Corticotropin-releasing factor (CRF) is crucial for regulating physiological and endocrine responses, triggering the activation of the sympathetic nervous system and the hypothalamo-pituitary-adrenal axis (HPA) during stress. In mammals, several telencephalic areas, such as the amygdala and the hippocampus, regulate the autonomic system and the HPA responses. These centers include subpopulations of CRF containing neurons that, by way of CRF receptors, play modulatory roles in the emotional and cognitive aspects of stress. CRF binding protein also plays a role, buffering extracellular CRF and regulating its availability. CRF role in activation of the HPA is evolutionary conserved in vertebrates, highlighting the relevance of this system to help animals cope with adversity. However, knowledge on CRF systems in the avian telencephalon is very limited, and no information exists on detailed expression of CRF receptors and binding protein. Knowing that the stress response changes with age, with important variations during the first week posthatching, the aim of this study was to analyze mRNA expression of CRF, CRF receptors 1 and 2, and CRF binding protein in chicken telencephalon throughout embryonic and early posthatching development, using in situ hybridization. Our results demonstrate an early expression of CRF and its receptors in pallial areas regulating sensory processing, sensorimotor integration and cognition, and a late expression in subpallial areas regulating the stress response. However, CRF buffering system develops earlier in the subpallium than in the pallium. These results help to understand the mechanisms underlying the negative effects of noise and light during prehatching stages in chicken, and suggest that stress regulation becomes more sophisticated with age.
... In contrast, pallial inputs preferentially targeted DL, much like they target the entorhinal cortex in mammals (Burwell and Amaral, 1998). Previous work has demonstrated numerous anatomical and physiological similarities of DL and the entorhinal cortex (Atoji and Wild, 2004;Abellán et al., 2014;Applegate et al., 2023). Our findings add further evidence of the equivalence between these regions across species. ...
... One possibility is that both the transverse and the long axes are derived from a common amniote precursor, and that these gradients of input have been preserved over millions of years (Witter et al., 2017;Herold et al., 2019). Indeed, similar transcription factors are expressed along the transverse axes across species (Abellán et al., 2014;Tosches et al., 2018). Conversely, similar topographies could have emerged through convergence. ...
The mammalian hippocampal formation (HF) is organized into domains associated with different functions. These differences are driven in part by the pattern of input along the hippocampal long axis, such as visual input to the septal hippocampus and amygdalar input to temporal hippocampus. HF is also organized along the transverse axis, with different patterns of neural activity in the hippocampus and the entorhinal cortex. In some birds, a similar organization has been observed along both of these axes. However, it is not known what role inputs play in this organization. We used retrograde tracing to map inputs into HF of a food-caching bird, the black-capped chickadee. We first compared two locations along the transverse axis: the hippocampus and the dorsolateral hippocampal area (DL), which is analogous to the entorhinal cortex. We found that pallial regions predominantly targeted DL, while some subcortical regions like the lateral hypothalamus (LHy) preferentially targeted the hippocampus. We then examined the hippocampal long axis and found that almost all inputs were topographic along this direction. For example, the anterior hippocampus was preferentially innervated by thalamic regions, while posterior hippocampus received more amygdalar input. Some of the topographies we found bear resemblance to those described in the mammalian brain, revealing a remarkable anatomical similarity of phylogenetically distant animals. More generally, our work establishes the pattern of inputs to HF in chickadees. Some of these patterns may be unique to chickadees, laying the groundwork for studying the anatomical basis of these birds' exceptional hippocampal memory.
... The overall dorsomedial/ventrolateral separation observed in our tracings stands seemingly in contrast to the nonlaminar appearance of the avian HF. More recent evidence suggests, however, that the avian HF displays a laminar organization (Abellán et al., 2014;Fujita et al., 2022;Redies et al., 2001). For instance, a subset of serotonergic receptors is expressed in a laminar fashion in 1-day-old chickens (Fujita et al., 2022). ...
... These layers are organized orthogonal to the orientation of radial glia (Abellán et al., 2014) and can be visualized with staining against calcium-binding proteins, neuronal nitric oxide synthase, and GABA in adult chicken (Suárez et al., 2006). Based on this finding, it was suggested that the ventral and dorsal subdivisions of the avian DL might correspond to deep versus superficial hippocampal layers in mammals, respectively (Medina et al., 2017). ...
... For the CDL and DL, the picture is less clear as both have already been compared to the EC (Atoji & Wild, 2004Abellán et al., 2014;Atoji et al., 2016;Herold et al., 2014Herold et al., , 2015. However, more detailed studies on CDL connectivity, which did not only investigate its connectivity to HF but also connections with other structures, came to the conclusion that CDL might be more similar to the cingulate cortex (Atoji & Wild, 2005). ...
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.
... Five weeks in-vitro (5WIV) differentiated neurons showed, by RNA-Seq, enriched expression of neuronal marker genes such as MAP2, TUBB3 and DLG4 (Table ST3). The differentiated neurons had enriched expression of ZBTB20, LHX9, ELAVL2 and TSPAN7 which are known hippocampus marker genes [26,29,30] (Table ST3). Differential gene expression analysis via DESeq2 revealed upregulation of 15 known markers for rodent and human CA3 (and CA2) in differentiated neurons (vs NPCs) (Table ST3). ...
Suicide is a condition resulting from complex environmental and genetic risks that affect millions of people globally. Both structural and functional studies identified the hippocampus as one of the vulnerable brain regions contributing to suicide risk. Here, we have identified the hippocampal transcriptomes, gene ontology, cell type proportions, dendritic spine morphology, and transcriptomic signature in iPSC-derived neuronal precursor cells (NPCs) and neurons in postmortem brain tissue from suicide deaths. The hippocampal tissue transcriptomic data revealed that NPAS4 gene expression was downregulated while ALDH1A2, NAAA , and MLXIPL gene expressions were upregulated in tissue from suicide deaths. The gene ontology identified 29 significant pathways including NPAS4 -associated gene ontology terms “excitatory post-synaptic potential”, “regulation of postsynaptic membrane potential” and “long-term memory” indicating alteration of glutamatergic synapses in the hippocampus of suicide deaths. The cell type deconvolution identified decreased excitatory neuron proportion and an increased inhibitory neuron proportion providing evidence of excitation/inhibition imbalance in the hippocampus of suicide deaths. In addition, suicide deaths had increased dendric spine density, due to an increase of thin (relatively unstable) dendritic spines, compared to controls. The transcriptomes of iPSC-derived hippocampal-like NPCs and neurons revealed 31 and 33 differentially expressed genes in NPC and neurons, respectively, of suicide deaths. The suicide-associated differentially expressed genes in NPCs were RELN, CRH, EMX2, OXTR, PARM1 and IFITM2 which overlapped with previously published results. The previously-known suicide-associated differentially expressed genes in differentiated neurons were COL1A1, THBS1, IFITM2, AQP1 , and NLRP2 . Together, these findings would help better understand the hippocampal neurobiology of suicide for identifying therapeutic targets to prevent suicide.
... Similar to functional gradients observed along the dorsoventral axis in mammals, several studies propose a comparable functional gradient along the rostrocaudal axis of the avian Hp. Studies of connectivity [26], gene expression [27,28], and place cell characteristics [29] all suggest similarities between the rostral pole of the avian Hp (rHp) and the dorsal pole of the mammalian Hp (see [30] for review). What remains unknown is whether the caudal pole of the avian Hp (cHp) is functionally comparable to the ventral pole of the mammalian Hp and, if so, is there a functional dissociation between the rostral and caudal poles? ...
The mammalian hippocampus (Hp) can be functionally segregated along its septotemporal axis, with involvement of dorsal hippocampus (dHp) in spatial memory and ventral hippocampus (vHp) in stress responses and emotional behaviour. In the present study, we investigate comparable functional segregation in proposed homologues within the avian brain. Using Japanese quail (Coturnix Japonica), we report that bilateral lesions of the rostral hippocampus (rHp) produce robust deficits in a spatial Y-maze discrimination (YMD) test while sparing performance during contextual fear conditioning (CFC), comparable to results from lesions to homologous regions in mammals. In contrast, caudal hippocampus (cHp) lesions failed to produce deficits in either CFC or YMD, suggesting that, unlike mammals, both cHp and rHp of birds can support emotional behavior. These observations demonstrate functional segregation along the rostrocaudal axis of the avian Hp that is comparable in part to distinctions seen along the mammalian hippocampal septotemporal axis.
... Although there is currently an intense debate about the subdivisions that constitute the pallial region, their derivatives and boundaries (Abellán et al., 2014;Puelles, 2017Puelles, , 2021Desfilis et al., 2018;Medina et al., 2021), numerous studies have demonstrated similarities between the mammalian hippocampal formation (HF) and derivatives of the medial pallium (MP) in the rest of vertebrates [for review see Butler (2017)] speaking for the homology of these structures. Topologically, the mammalian HF is located in the mediodorsal area of the telencephalon, bordered rostrally by the indusium griseum and the dorsal tenia tecta (Wyss and Sripanidkulchai, 1983;Künzle, 2004;Laplante et al., 2013). ...
... In adults, this cortical structure is composed of a central region, that shows a characteristic C-shape organized in three layers and the parahippocampal region [for a review see Amaral and Lavenex (2009)]. Similarities at the functional, hodological and cellular levels have been proposed between the HF and the MP of the rest of the amniotes (Filimonoff, 1964;Karten and Hodos, 1967;Bingman and Yates, 1992;Striedter, 1997;Puelles et al., 2000;Lohmann et al., 2004;Atoji and Wild, 2006;Kahn and Bingman, 2009;Mayer et al., 2013;Abellán et al., 2014;Naumann et al., 2015;Reiter et al., 2017;Gupta et al., 2020;Schede et al., 2021). But it is mostly in mammals where the neurogenesis of this region has been extensively studied (Sugiyama et al., 2013;Zhang and Jiao, 2015) and specifically the maintenance of this neurogenic capacity in adults (Alvarez-Buylla and Lim, 2004;Gould, 2007;Kempermann et al., 2015). ...
... Abbreviations: BG, basal ganglia; BST, bed nucleus of the stria terminalis; CeA, central amygdala; CH, cortical hem; ChP, choroid plexus; cpal, pallial commissure; DCx, dorsal cortex; DMCx, dorso-medial cortex; DMP, dorso-medial pallium; DP, dorsal pallium; DVR, dorsal ventricular ridge; LCx, lateral cortex; LP, lateral pallium; MCx, medial cortex; MeA, medial amygdala; MP, medial pallium; oc, optic chiasm; Pa, pallium; pa, pallidum; POA, preoptic area; PT, pallial thickening; S, septum; Sd, dorsal septum; SPa, subpallium; Str, striatum; SPV, supraoptoparaventricular area; Th, thalamus; v, ventricle; vz, ventricular zone; VP, ventral pallium. In this context, although evolutionary knowledge of this region has increased significantly in recent years (Abellán et al., 2014;Medina et al., 2017;Tosches et al., 2018;Woych et al., 2022), we still lack a detailed comparative analysis of the expression pattern of conserved MP developmental genes (usually used as markers to identify the mammalian MP) during development and in the adult in non-mammalian species. ...
In all vertebrates, the most dorsal region of the telencephalon gives rise to the pallium, which in turn, is formed by at least four evolutionarily conserved histogenetic domains. Particularly in mammals, the medial pallium generates the hippocampal formation. Although this region is structurally different among amniotes, its functions, attributed to spatial memory and social behavior, as well as the specification of the histogenetic domain, appears to be conserved. Thus, the aim of the present study was to analyze this region by comparative analysis of the expression patterns of conserved markers in two vertebrate models: one anamniote, the amphibian Xenopus laevis ; and the other amniote, the turtle Trachemys scripta elegans , during development and in adulthood. Our results show that, the histogenetic specification of both models is comparable, despite significant cytoarchitectonic differences, in particular the layered cortical arrangement present in the turtle, not found in anurans. Two subdivisions were observed in the medial pallium of these species: a Prox1 + and another Er81/Lmo4 +, comparable to the dentate gyrus and the mammalian cornu ammonis region, respectively. The expression pattern of additional markers supports this subdivision, which together with its functional involvement in spatial memory tasks, provides evidence supporting the existence of a basic program in the specification and functionality of the medial pallium at the base of tetrapods. These results further suggest that the anatomical differences found in different vertebrates may be due to divergences and adaptations during evolution.
... It consists of densely packed heterogeneous populations of neurons and it is not clearly distinguished from adjacent telencephalic structures. However, recent studies using detailed anatomical analysis of immunohistochemical and gene expression markers revealed the existence of layers in domestic chicks' and adult chickens' hippocampal formation (hippocampus proper and area parahippocampalis; Redies et al., 2001;Suárez et al., 2006;Abellán et al., 2014;Fujita et al., 2020, see Figure 1E; see Herold et al., 2019 for similar evidence in adult pigeons). This suggests that hippocampal layers are an ancestral trait at least among sauropsids. ...
In this review, we discuss the functional equivalence of the avian and mammalian hippocampus, based mostly on our own research in domestic chicks, which provide an important developmental model (most research on spatial cognition in other birds relies on adult animals). In birds, like in mammals, the hippocampus plays a central role in processing spatial information. However, the structure of this homolog area shows remarkable differences between birds and mammals. To understand the evolutionary origin of the neural mechanisms for spatial navigation, it is important to test how far theories developed for the mammalian hippocampus can also be applied to the avian hippocampal formation. To address this issue, we present a brief overview of studies carried out in domestic chicks, investigating the direct involvement of chicks’ hippocampus homolog in spatial navigation.
