RESUMEN

Crocodilians (alligators, crocodiles, and gharials) are the closet living relatives to birds and, as such, represent a key clade to understand the evolution of the avian brain. However, many aspects of crocodilian neurobiology remain unknown. In this paper, we address an important knowledge gap as there are no published studies of cerebellar connections in any crocodilian species. We used injections of retrograde tracers into the cerebellum of the American alligator (Alligator mississippiensis) to describe for the first time the origin of climbing and mossy fiber inputs. We found that inputs to the cerebellum in the American alligator are similar to those of other nonavian reptiles and birds. Retrograde labeled cells were found in the spinal cord, inferior olive, reticular formation, vestibular and cerebellar nuclei, as well as in nucleus ruber and surrounding tegmentum. Additionally, we found no retrogradely labeled cells in the anterior rhombencephalon which suggest that, like other nonavian reptiles, crocodilians may lack pontine nuclei. Similar to birds and other nonavian reptiles, we found inputs to the cerebellum from the pretectal nucleus lentiformis mesencephali. Additionally, we found retrogradely labeled neurons in two nuclei in the pretectum: the nucleus circularis and the interstitial nucleus of the posterior commissure. These pretectal projections have not been described in any other nonavian reptile to date, but they do resemble projections from the nucleus spiriformis medialis of birds. Our results show that many inputs to the cerebellum are highly conserved among sauropsids and that extensive pretectal inputs to the cerebellum are not exclusive to the avian brain. Finally, we suggest that the pontine nuclei of birds are an evolutionary novelty that may have evolved after the last common ancestor between birds and crocodilians, and may represent an intriguing case of convergent evolution with mammals.

Asunto(s)

Caimanes y Cocodrilos , Animales , Cerebelo , Tegmento Mesencefálico , Neuronas , Médula Espinal , Mamíferos

RESUMEN

Time-related cognitive function refers to the capacity of the brain to store, extract, and process specific information. Previous studies demonstrated that the cerebellar cortex participates in advanced cognitive functions, but the role of the cerebellar cortex in cognitive functions is unclear. We established a behavioral model using classical eyeblink conditioning to study the role of the cerebellar cortex in associative learning and memory and the underlying mechanisms. We performed an investigation to determine whether eyeblink conditioning could be established by placing the stimulating electrode in the middle cerebellar peduncle. Behavior training was performed using a microcurrent pulse as a conditioned stimulus to stimulate the middle cerebellar peduncle and corneal blow as an unconditioned stimulus. After 10 consecutive days of training, a conditioned response was successfully achieved in the Delay, Trace-200-ms, and Trace-300-ms groups of guinea pigs, with acquisition rates of >60%, but the Trace-400-ms and control groups did not achieve a conditioned stimulus-related blink conditioned response. It could be a good model for studying the function of the cerebellum during the establishment of eyeblink conditioning.

RESUMEN

Axonal projections from layer V neurons of distinct neocortical areas are topographically organized into discrete clusters within the pontine nuclei during the establishment of voluntary movements. However, the molecular determinants controlling corticopontine connectivity are insufficiently understood. Here, we show that an intrinsic cortical genetic program driven by Nr2f1 graded expression is directly implicated in the organization of corticopontine topographic mapping. Transgenic mice lacking cortical expression of Nr2f1 and exhibiting areal organization defects were used as model systems to investigate the arrangement of corticopontine projections. By combining three-dimensional digital brain atlas tools, Cre-dependent mouse lines and axonal tracing, we show that Nr2f1 expression in postmitotic neurons spatially and temporally controls somatosensory topographic projections, whereas expression in progenitor cells influences the ratio between corticopontine and corticospinal fibres passing the pontine nuclei. We conclude that cortical gradients of area-patterning genes are directly implicated in the establishment of a topographic somatotopic mapping from the cortex onto pontine nuclei.

Asunto(s)

Mapeo Encefálico , Puente , Animales , Axones , Corteza Cerebral , Ratones , Vías Nerviosas/fisiología , Neuronas , Puente/fisiología

RESUMEN

This chapter summarizes early electrophysiological and lesion studies to elucidate cortical, subcortical and cerebellar mechanisms for extracting visual target motion and programming a smooth-pursuit response. The importance of a descending pursuit pathway from the middle temporal (MT) cortical visual area, which extracts the speed and direction of a moving target, the projections to dorsolateral pontine nuclei, and onto the cerebellum are outlined. Contributions of the cerebellum to pursuit are discussed and models are presented to account for the ways in which floccular gaze Purkinje cells behave during smooth pursuit, combined eye-head tracking, and during head rotation while viewing a stationary target.

Asunto(s)

Seguimiento Ocular Uniforme , Reflejo Vestibuloocular , Cerebelo/fisiología , Humanos , Neurofisiología , Células de Purkinje/fisiología , Reflejo Vestibuloocular/fisiología

RESUMEN

The arcuate nucleus (Arc) of the medulla is found in almost all human brains and in a small percentage of chimpanzee brains. It is absent in the brains of other mammalian species including mice, rats, cats, and macaque monkeys. The Arc is classically considered a precerebellar relay nucleus, receiving input from the cerebral cortex and projecting to the cerebellum via the inferior cerebellar peduncle. However, several studies have found aplasia of the Arc in babies who died of SIDS (Sudden Infant Death Syndrome), and it was suggested that the Arc is the locus of chemosensory neurons critical for brainstem control of respiration. Aplasia of the Arc, however, has also been reported in adults, suggesting that it is not critical for survival. We have examined the Arc in closely spaced Nissl-stained sections in thirteen adult human cases to acquire a better understanding of the degree of variability of its size and location in adults. We have also examined immunostained sections to look for neurochemical compartments in this nucleus. Caudally, neurons of the Arc are ventrolateral to the pyramidal tracts (py); rostrally, they are ventro-medial to the py and extend up along the midline. In some cases, the Arc is discontinuous, with a gap between sections with the ventrolaterally located and the ventromedially located neurons. In all cases, there is some degree of left-right asymmetry in Arc position, size, and shape at all rostro-caudal levels. Somata of neurons in the Arc express calretinin (CR), neuronal nitric oxide synthase (nNOS), and nonphosphorylated neurofilament protein (NPNFP). Calbindin (CB) is expressed in puncta whereas there is no expression of parvalbumin (PV) in somata or puncta. There is also immunostaining for GAD and GABA receptors suggesting inhibitory input to Arc neurons. These properties were consistent among cases. Our data show differences in location of caudal and rostral Arc neurons and considerable variability among cases in the size and shape of the Arc. The variability in size suggests that "hypoplasia" of the Arc is difficult to define. The discontinuity of the Arc in many cases suggests that establishing aplasia of the Arc requires examination of many closely spaced sections through the brainstem.

Asunto(s)

Núcleo Arqueado del Hipotálamo , Bulbo Raquídeo , Núcleo Arqueado del Hipotálamo/metabolismo , Tronco Encefálico/metabolismo , Calbindinas , Humanos , Bulbo Raquídeo/metabolismo , Proteínas de Neurofilamentos/metabolismo

RESUMEN

Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen α3 VI (COL6A3) C-terminal domain (CTD). These Col6a3CTT mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3CTT mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid (eCB) signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3CTT mice of both sexes was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control.SIGNIFICANCE STATEMENT Dystonia is a movement disorder characterized by involuntary movements. We previously identified genetic variants affecting a specific domain of the COL6A3 protein as a cause of dystonia. Here, we created mice lacking the affected domain and observed an analogous movement disorder. Using a protein interaction screen, we found that the affected COL6A3 domain mediates an interaction with the cannabinoid receptor 1 (CB1R). Concordantly, our COL6A3-deficient mice showed a deficit in synaptic plasticity linked to a deficit in cannabinoid signaling. Pharmacological cannabinoid augmentation rescued the motor impairment of the mice. Thus, cannabinoid augmentation could be a promising avenue for treating dystonia, and we have identified a possible molecular mechanism mediating this.

Asunto(s)

Cannabinoides , Colágeno Tipo VI , Distonía , Trastornos Distónicos , Neuronas Motoras , Plasticidad Neuronal , Animales , Cannabinoides/metabolismo , Cannabinoides/farmacología , Colágeno Tipo VI/genética , Colágeno Tipo VI/metabolismo , Distonía/genética , Distonía/metabolismo , Trastornos Distónicos/genética , Trastornos Distónicos/metabolismo , Femenino , Masculino , Ratones , Neuronas Motoras/efectos de los fármacos , Mutación , Plasticidad Neuronal/efectos de los fármacos , Receptores de Cannabinoides/genética , Receptores de Cannabinoides/metabolismo

RESUMEN

The brainstem includes many nuclei and fiber tracts that mediate a wide range of functions. Data from two parallel approaches to the study of autistic spectrum disorder (ASD) implicate many brainstem structures. The first approach is to identify the functions affected in ASD and then trace the neural systems mediating those functions. While not included as core symptoms, three areas of function are frequently impaired in ASD: (1) Motor control both of the limbs and body and the control of eye movements; (2) Sensory information processing in vestibular and auditory systems; (3) Control of affect. There are critical brainstem nuclei mediating each of those functions. There are many nuclei critical for eye movement control including the superior colliculus. Vestibular information is first processed in the four nuclei of the vestibular nuclear complex. Auditory information is relayed to the dorsal and ventral cochlear nuclei and subsequently processed in multiple other brainstem nuclei. Critical structures in affect regulation are the brainstem sources of serotonin and norepinephrine, the raphe nuclei and the locus ceruleus. The second approach is the analysis of abnormalities from direct study of ASD brains. The structure most commonly identified as abnormal in neuropathological studies is the cerebellum. It is classically a major component of the motor system, critical for coordination. It has also been implicated in cognitive and language functions, among the core symptoms of ASD. This structure works very closely with the cerebral cortex; the cortex and the cerebellum show parallel enlargement over evolution. The cerebellum receives input from cortex via relays in the pontine nuclei. In addition, climbing fiber input to cerebellum comes from the inferior olive of the medulla. Mossy fiber input comes from the arcuate nucleus of the medulla as well as the pontine nuclei. The cerebellum projects to several brainstem nuclei including the vestibular nuclear complex and the red nucleus. There are thus multiple brainstem nuclei distributed at all levels of the brainstem, medulla, pons, and midbrain, that participate in functions affected in ASD. There is direct evidence that the cerebellum may be abnormal in ASD. The evidence strongly indicates that analysis of these structures could add to our understanding of the neural basis of ASD.

RESUMEN

To control reaching, the nervous system must generate large changes in muscle activation to drive the limb toward the target, and must also make smaller adjustments for precise and accurate behavior. Motor cortex controls the arm through projections to diverse targets across the central nervous system, but it has been challenging to identify the roles of cortical projections to specific targets. Here, we selectively disrupt cortico-cerebellar communication in the mouse by optogenetically stimulating the pontine nuclei in a cued reaching task. This perturbation did not typically block movement initiation, but degraded the precision, accuracy, duration, or success rate of the movement. Correspondingly, cerebellar and cortical activity during movement were largely preserved, but differences in hand velocity between control and stimulation conditions predicted from neural activity were correlated with observed velocity differences. These results suggest that while the total output of motor cortex drives reaching, the cortico-cerebellar loop makes small adjustments that contribute to the successful execution of this dexterous movement.

Asunto(s)

Núcleos Cerebelosos/fisiología , Corteza Motora/fisiología , Movimiento/fisiología , Vías Nerviosas , Animales , Ratones , Ratones Transgénicos , Optogenética

RESUMEN

Throughout mammalian neocortex, layer 5 pyramidal (L5) cells project via the pons to a vast number of cerebellar granule cells (GrCs), forming a fundamental pathway. Yet, it is unknown how neuronal dynamics are transformed through the L5→GrC pathway. Here, by directly comparing premotor L5 and GrC activity during a forelimb movement task using dual-site two-photon Ca2+ imaging, we found that in expert mice, L5 and GrC dynamics were highly similar. L5 cells and GrCs shared a common set of task-encoding activity patterns, possessed similar diversity of responses, and exhibited high correlations comparable to local correlations among L5 cells. Chronic imaging revealed that these dynamics co-emerged in cortex and cerebellum over learning: as behavioral performance improved, initially dissimilar L5 cells and GrCs converged onto a shared, low-dimensional, task-encoding set of neural activity patterns. Thus, a key function of cortico-cerebellar communication is the propagation of shared dynamics that emerge during learning.

Asunto(s)

Cerebelo/metabolismo , Neocórtex/metabolismo , Animales , Conducta Animal , Calcio/metabolismo , Miembro Anterior/fisiología , Ratones , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Neocórtex/patología , Opsinas/genética , Opsinas/metabolismo , Células Piramidales/metabolismo

RESUMEN

In this paper, we review the connections and physiology of visual pathways to the cerebellum in birds and consider their role in flight. We emphasize that there are two visual pathways to the cerebellum. One is to the vestibulocerebellum (folia IXcd and X) that originates from two retinal-recipient nuclei that process optic flow: the nucleus of the basal optic root (nBOR) and the pretectal nucleus lentiformis mesencephali (LM). The second is to the oculomotor cerebellum (folia VI-VIII), which receives optic flow information, mainly from LM, but also local visual motion information from the optic tectum, and other visual information from the ventral lateral geniculate nucleus (Glv). The tectum, LM and Glv are all intimately connected with the pontine nuclei, which also project to the oculomotor cerebellum. We believe this rich integration of visual information in the cerebellum is important for analyzing motion parallax that occurs during flight. Finally, we extend upon a suggestion by Ibbotson (2017) that the hypertrophy that is observed in LM in hummingbirds might be due to an increase in the processing demands associated with the pathway to the oculomotor cerebellum as they fly through a cluttered environment while feeding.

RESUMEN

Diverse and powerful mechanisms have evolved to enable organisms to modulate learning and memory under a variety of survival conditions. Cumulative evidence has shown that the prefrontal cortex (PFC) is closely involved in many higher-order cognitive functions. However, when and how the medial PFC (mPFC) modulates associative motor learning remains largely unknown. Here, we show that delay eyeblink conditioning (DEC) with the weak conditioned stimulus (wCS) but not the strong CS (sCS) elicited a significant increase in the levels of c-Fos expression in caudal mPFC. Both optogenetic inhibition and activation of the bilateral caudal mPFC, or its axon terminals at the pontine nucleus (PN) contralateral to the training eye, significantly impaired the acquisition, recent and remote retrieval of DEC with the wCS but not the sCS. However, direct optogenetic activation of the contralateral PN had no significant effect on the acquisition, recent and remote retrieval of DEC. These results are of great importance in understanding the elusive role of the mPFC and its projection to PN in subserving the associative motor learning under suboptimal learning cue.

Asunto(s)

Aprendizaje por Asociación/fisiología , Señales (Psicología) , Actividad Motora/fisiología , Vías Nerviosas/fisiología , Tegmento Pontino/fisiología , Corteza Prefrontal/fisiología , Animales , Proteínas de Unión al Calcio , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Condicionamiento Clásico , Potenciales Postsinápticos Excitadores/genética , Agonistas de Receptores de GABA-A/farmacología , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Muscimol/farmacología , Optogenética , Farmacogenética , Ratas , Ratas Sprague-Dawley , Transducción Genética

RESUMEN

In the last decade, the interplay between basal ganglia and cerebellar functions has been increasingly advocated to explain their joint operation in both normal and pathological conditions. Yet, insight into the neuroanatomical basis of this interplay between both subcortical structures remains sparse and is mainly derived from work in primates. Here, in rodents, we have studied the existence of a potential disynaptic connection between the subthalamic nucleus (STN) and the cerebellar cortex as has been demonstrated earlier for the primate. A mixture of unmodified rabies virus (RABV: CVS 11) and cholera toxin B-subunit (CTb) was injected at places in the posterior cerebellar cortex of nine rats. The survival time was chosen to allow for disynaptic retrograde transneuronal infection of RABV. We examined the STN for neurons infected with RABV in all nine cases and related the results with the location of the RABV/CTb injection site, which ranged from the vermis of lobule VII, to the paravermis and hemispheres of the paramedian lobule and crus 2a. We found that cases with injection sites in the vermis of lobule VII showed prominent RABV labeling in the STN. In contrast, almost no subthalamic labeling was noted in cases with paravermal or hemispheral injection sites. We show circumstantial evidence that not only the pontine nuclei but also the pedunculotegmental nucleus may act as the intermediary in the connection from STN to cerebellar cortex. This finding implies that in the rat the STN links disynaptically to the vermal part of lobule VII of the cerebellar cortex, without any major involvement of the cerebellar areas that are linked to sensorimotor functions. As vermal lobule VII recently has been shown to process disynaptic input from the retrosplenial and orbitofrontal cortices, we hypothesize that in the rat the subthalamic input to cerebellar function might be used to influence more prominently non-motor functions of the cerebellum than motor functions. This latter aspect seems to contradict the primate results and could point to a more elaborate interaction between basal ganglia and cerebellum in more demanding motor tasks.

RESUMEN

How do the hippocampus and amygdala interact with thalamocortical systems to regulate cognitive and cognitive-emotional learning? Why do lesions of thalamus, amygdala, hippocampus, and cortex have differential effects depending on the phase of learning when they occur? In particular, why is the hippocampus typically needed for trace conditioning, but not delay conditioning, and what do the exceptions reveal? Why do amygdala lesions made before or immediately after training decelerate conditioning while those made later do not? Why do thalamic or sensory cortical lesions degrade trace conditioning more than delay conditioning? Why do hippocampal lesions during trace conditioning experiments degrade recent but not temporally remote learning? Why do orbitofrontal cortical lesions degrade temporally remote but not recent or post-lesion learning? How is temporally graded amnesia caused by ablation of prefrontal cortex after memory consolidation? How are attention and consciousness linked during conditioning? How do neurotrophins, notably brain-derived neurotrophic factor (BDNF), influence memory formation and consolidation? Is there a common output path for learned performance? A neural model proposes a unified answer to these questions that overcome problems of alternative memory models.

Asunto(s)

Aprendizaje/fisiología , Consolidación de la Memoria/fisiología , Modelos Neurológicos , Adaptación Psicológica/fisiología , Amnesia/fisiopatología , Amígdala del Cerebelo/fisiología , Animales , Parpadeo/fisiología , Corteza Cerebral/fisiología , Condicionamiento Psicológico/fisiología , Estado de Conciencia/fisiología , Retroalimentación , Hipocampo/fisiología , Humanos , Factores de Crecimiento Nervioso/metabolismo , Vías Nerviosas/fisiología , Neuronas/fisiología , Tálamo/fisiología

RESUMEN

Trace eyeblink conditioning is useful for studying the interaction of multiple brain areas in learning and memory. The goal of the current work was to determine whether trace eyeblink conditioning could be established in a mouse model in the absence of elicited startle responses and the brain circuitry that supports this learning. We show here that mice can acquire trace conditioned responses (tCRs) devoid of startle while head-restrained and permitted to freely run on a wheel. Most mice (75%) could learn with a trace interval of 250 ms. Because tCRs were not contaminated with startle-associated components, we were able to document the development and timing of tCRs in mice, as well as their long-term retention (at 7 and 14 d) and flexible expression (extinction and reacquisition). To identify the circuitry involved, we made restricted lesions of the medial prefrontal cortex (mPFC) and found that learning was prevented. Furthermore, inactivation of the cerebellum with muscimol completely abolished tCRs, demonstrating that learned responses were driven by the cerebellum. Finally, inactivation of the mPFC and amygdala in trained animals nearly abolished tCRs. Anatomical data from these critical regions showed that mPFC and amygdala both project to the rostral basilar pons and overlap with eyelid-associated pontocerebellar neurons. The data provide the first report of trace eyeblink conditioning in mice in which tCRs were driven by the cerebellum and required a localized region of mPFC for acquisition. The data further reveal a specific role for the amygdala as providing a conditioned stimulus-associated input to the cerebellum.

RESUMEN

More studies are required to develop therapeutic agents for treating spinocerebellar ataxia type 3 (SCA3), which is caused by mutant polyglutamine-expanded ataxin-3 and is the most prevalent subtype of spinocerebellar ataxias. T1-11 [N6-(4-Hydroxybenzyl) adenosine], isolated from a Chinese medicinal herb Gastordia elata, is an adenosine A2A receptor agonist. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. T1-11 exerted a therapeutic effect on HD transgenic mouse by decreasing protein level of polyglutamine-expanded huntingtin in the striatum. In the present study, we test the possibility that T1-11 or JMF1907 [N6-(3-Indolylethyl) adenosine], a synthetic analog of T1-11, alleviates pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom in the SCA3 transgenic mouse expressing HA-tagged polyglutamine-expanded ataxin-3-Q79 (ataxin-3-Q79HA). Daily oral administration of T1-11 or JMF1907 prevented neuronal death of pontine nuclei in the SCA3 mouse with a dose-dependent manner. Oral application of T1-11 or JMF1907 reversed mutant ataxin-3-Q79-induced cerebellar transcriptional repression in the SCA3 transgenic mouse. T1-11 or JMF1907 ameliorated the symptom of motor incoordination displayed by SCA3 mouse. Oral administration of T1-11 or JMF1907 significantly decreased protein level of ataxin-3-Q79HA in the pontine nuclei or cerebellum of SCA3 mouse. T1-11 or JMF1907 significantly augmented the chymotrypsin-like activity of proteasome in the pontine nuclei or cerebellum of SCA3 mouse. Our results suggests that T1-11 and JMF1907 alleviate pontine neuronal death, cerebellar transcriptional downregulation and ataxic symptom of SCA3 transgenic mouse by augmenting the proteasome activity and reducing the protein level of polyglutamine-expanded ataxin-3-Q79 in the pontine nuclei and cerebellum.

Asunto(s)

Adenosina/análogos & derivados , Indoles/farmacología , Enfermedad de Machado-Joseph/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Adenosina/farmacología , Administración Oral , Animales , Ataxina-3/genética , Ataxina-3/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Cerebelo/patología , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Humanos , Enfermedad de Machado-Joseph/patología , Enfermedad de Machado-Joseph/fisiopatología , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuronas/efectos de los fármacos , Neuronas/patología , Puente/efectos de los fármacos , Puente/metabolismo , Puente/patología , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismo

RESUMEN

The calcium ion regulates many aspects of neuronal migration, which is an indispensable process in the development of the nervous system. Calmodulin (CaM) is a multifunctional calcium ion sensor that transduces much of the signal. To better understand the role of Ca(2+)-CaM in neuronal migration, we investigated mouse precerebellar neurons (PCNs), which undergo stereotyped, long-distance migration to reach their final position in the developing hindbrain. In mammals, CaM is encoded by three non-allelic CaM (Calm) genes (Calm1, Calm2 and Calm3), which produce an identical protein with no amino acid substitutions. We found that these CaM genes are expressed in migrating PCNs. When the expression of CaM from this multigene family was inhibited by RNAi-mediated acute knockdown, inhibition of Calm1 but not the other two genes caused defective PCN migration. Many PCNs treated with Calm1 shRNA failed to complete their circumferential tangential migration and thus failed to reach their prospective target position. Those that did reach the target position failed to invade the depth of the hindbrain through the required radial migration. Overall, our results suggest the participation of CaM in both the tangential and radial migration of PCNs.

Asunto(s)

Calmodulina/metabolismo , Movimiento Celular/fisiología , Cerebelo/embriología , Neuronas/fisiología , Transducción de Señal/fisiología , Animales , Células COS , Calcio/metabolismo , Chlorocebus aethiops , Cartilla de ADN/genética , Inmunohistoquímica , Hibridación in Situ , Ratones , Plásmidos/genética , Interferencia de ARN

RESUMEN

The caudal part of the macaque ventrolateral prefrontal (VLPF) cortex hosts several distinct areas or fields--45B, 45A, 8r, caudal 46vc, and caudal 12r--connected to the frontal eye field (area 8/FEF). To assess whether these areas/fields also display subcortical projections possibly mediating a role in controlling oculomotor behavior, we examined their descending projections, based on anterograde tracer injections in each area/field, and compared them with those of area 8/FEF. All the studied areas/fields displayed projections to brainstem preoculomotor structures, precerebellar centers, and striatal sectors that are also targets of projections originating from area 8/FEF. Specifically, these projections involved: (1) the intermediate and superficial layers of the superior colliculus; (2) the mesencephalic and pontine reticular formation; (3) the dorsomedial and lateral pontine nuclei and the reticularis tegmenti pontis; and (4) the body of the caudate nucleus. Furthermore, area 45B projected also to the regions around the trochlear nucleus and to the raphe interpositus. The present data provide evidence for a role of the caudal VLPF areas/fields in controlling oculomotor behavior not only through their connections to area 8/FEF, but also in parallel through a direct access to preoculomotor brainstem structures and to the cerebellar and basal ganglia oculomotor loops.

Asunto(s)

Ganglios Basales/citología , Tronco Encefálico/citología , Cerebelo/citología , Movimientos Oculares , Corteza Prefrontal/citología , Animales , Núcleo Caudado/citología , Macaca fascicularis , Macaca mulatta , Vías Nerviosas/citología , Técnicas de Trazados de Vías Neuroanatómicas , Tegmento Pontino/citología , Colículos Superiores/citología , Tegmento Mesencefálico/citología

RESUMEN

The medial prefrontal cortex (mPFC) of both rats and rabbits has been shown to support trace eyeblink conditioning, presumably by providing an input to the cerebellum via the pons that bridges the temporal gap between conditioning stimuli. The pons of rats and rabbits, however, shows divergence in gross anatomical organization, leaving open the question of whether the topography of prefrontal inputs to the pons is similar in rats and rabbits. To investigate this question, we injected anterograde tracer into the mPFC of rats and rabbits to visualize and map in 3D the distribution of labeled terminals in the pons. Effective mPFC injections showed labeled axons in the ipsilateral descending pyramidal tract in both species. In rats, discrete clusters of densely labeled terminals were observed primarily in the rostromedial pons. Clusters of labeled terminals were also observed contralateral to mPFC injection sites in rats, appearing as a less dense "mirror-image" of ipsilateral labeling. In rabbits, mPFC labeled corticopontine terminals were absent in the rostral pons, and instead were restricted to the intermediate pons. The densest terminal fields were typically observed in association with the ipsilateral pyramidal tract as it descended ventromedially through the rabbit pons. No contralateral terminal labeling was observed for any injections made in the rabbit mPFC. The results suggest the possibility that mPFC inputs to the pons may be integrated with different sources of cortical inputs between rats and rabbits. The resulting implications for mPFC or pons manipulations for studies of trace eyeblink in each species are discussed.

Asunto(s)

Vías Eferentes/fisiología , Puente/anatomía & histología , Corteza Prefrontal/anatomía & histología , Animales , Dextranos/metabolismo , Colorantes Fluorescentes/metabolismo , Lateralidad Funcional , Imagenología Tridimensional , Masculino , Microscopía Fluorescente , Conejos , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie

RESUMEN

Prolyl carboxypeptidase (PRCP), a serine protease, is widely expressed in the body including liver, lung, kidney and brain, with a variety of known substrates such as plasma prekallikrein, bradykinin, angiotensins II and III, and α-MSH, suggesting its role in the processing of tissue-specific substrates. In the brain, PRCP has been shown to inactivate hypothalamic α-MSH, thus modulating melanocortin signaling in the control of energy metabolism. While its expression pattern has been reported in the hypothalamus, little is known on the distribution of PRCP throughout the mouse brain. This study was undertaken to determine PRCP expression in the mouse brain. Radioactive in situ hybridization was performed to determine endogenous PRCP mRNA expression. In addition, using a gene-trap mouse model for PRCP deletion, X-gal staining was performed to further determine PRCP distribution. Results from both approaches showed that PRCP gene is broadly expressed in the brain.

Asunto(s)

Encéfalo/enzimología , Carboxipeptidasas/genética , Carboxipeptidasas/metabolismo , ARN Mensajero/metabolismo , Animales , Galactósidos/metabolismo , Expresión Génica , Indoles/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos

RESUMEN

The mammalian brain is characterized by orderly spatial distribution of its cellular components, commonly referred to as topographical organization. The topography of cortical and subcortical maps is thought to represent functional or computational properties. In the present investigation, we have studied map transformations and organizing principles in the projections from the cerebral cortex to the pontine nuclei, with emphasis on the mapping of the cortex as a whole onto the pontine nuclei. Following single or multiple axonal tracer injections into different cortical regions, three-dimensional (3-D) distributions of anterogradely labeled axons in the pontine nuclei were mapped. All 3-D reconstructed data sets were normalized to a standardized local coordinate system for the pontine nuclei and uploaded in a database application (FACCS, Functional Anatomy of the Cerebro-Cerebellar System, available via The Rodent Brain Workbench, http://www.rbwb.org). The database application allowed flexible use of the data in novel combinations, and use of a previously published data sets. Visualization of different combinations of data was used to explore alternative principles of organization. As a result of these analyses, a principal map of the topography of corticopontine projections was developed. This map followed the organization of early spatiotemporal gradients present in the cerebral cortex and the pontine nuclei. With the principal map for corticopontine projections, a fairly accurate prediction of pontine target area can be made for any site of origin in the cerebral cortex. The map and the underlying shared data sets represent a basis for modeling of topographical organization and structure-function relationships in this system.