Antagonism between Notch and bone morphogenetic protein receptor signaling regulates neurogenesis in the cerebellar rhombic lip

Background

During the embryonic development of the cerebellum, neurons are produced from progenitor cells located along a ventricular zone within dorsal rhombomere 1 that extends caudally to the roof plate of the fourth ventricle. The apposition of the caudal neuroepithelium and roof plate results in a unique inductive region termed the cerebellar rhombic lip, which gives rise to granule cell precursors and other glutamatergic neuronal lineages. Recently, we and others have shown that, at early embryonic stages prior to the emergence of granule cell precursors (E12), waves of neurogenesis in the cerebellar rhombic lip produce specific hindbrain nuclei followed by deep cerebellar neurons. How the induction of rhombic lip-derived neurons from cerebellar progenitors is regulated during this phase of cerebellar development to produce these temporally discrete neuronal populations while maintaining a progenitor pool for subsequent neurogenesis is not known.

Results

Employing both gain- and loss-of-function methods, we find that Notch1 signaling in the cerebellar primordium regulates the responsiveness of progenitor cells to bone morphogenetic proteins (BMPs) secreted from the roof plate that stimulate the production of rhombic lip-derived neurons. In the absence of Notch1, cerebellar progenitors are depleted during the early production of hindbrain neurons, resulting in a severe decrease in the deep cerebellar nuclei that are normally born subsequently. Mechanistically, we demonstrate that Notch1 activity prevents the induction of Math1 by antagonizing the BMP receptor-signaling pathway at the level of Msx2 expression.

Conclusion

Our results provide a mechanism by which a balance between neural induction and maintenance of neural progenitors is achieved in the rhombic lip throughout embryonic development.     

Anatomical gradients of adult neurogenesis and activity: Young neurons in the ventral dentate gyrus are activated by water maze training

Hippocampal function varies in a subregion‐specific fashion: spatial processing is thought to rely on the dorsal hippocampus, whereas anxiety‐related behavior relies more on the ventral hippocampus. During development, neurogenesis in the dentate gyrus (DG) proceeds along ventral to dorsal as well as suprapyramidal to infrapyramidal gradients, but it is unclear whether regional differences in neurogenesis are maintained in adulthood. Moreover, it is unknown whether young neurons in the adult exhibit subregion‐specific patterns of activation. We therefore examined the magnitude of neurogenesis and the activation of young and mature granule cells in DG subregions in adult rats that learned a spatial water maze task, swam with no platform, or were left untouched. We found that both adult neurogenesis and granule cell activation, as defined by c‐fos expression in the granule cell population as a whole, were higher in the dorsal than the ventral DG. In contrast, c‐fos expression in adult‐born granule cells, identified by PSA‐NCAM or location in the subgranular zone, occurred at a higher rate in the opposite subregion, the ventral DG. Interestingly, c‐fos expression in the entire granule cell population was equivalent in water maze‐trained rats and swim control rats, but was increased in the young granule cells only in the learning condition. These results provide new evidence that hippocampally‐relevant experience activates young and mature neurons in different DG subregions and with different experiential specificity, and suggest that adult‐born neurons may play a specific role in anxiety‐related behavior or other nonspatial aspects of hippocampal function. © 2008 Wiley‐Liss, Inc.     

Neocortical transplants in the micrencephalic rat brain: Morphology and behavior

Normal fetal (E18) neocortical tissue transplanted into the hypoplastic posterior neocortex of infant (10 +/- 2-day-old) rats with transplacentally induced micrencephaly developed into very large, healthy, and permanent transplants. Although the cellular organization within the transplants rarely resembled that of normal rat neocortex, the transplants formed a broad area of interface with the host brain and established fiber connections with it. When tested at 2 months and 1-year-of-age, the presence of the transplant had no significant effect on the typically abnormal performance of micrencephalic rats on two tests of unspecific function, open field activity and maze learning. However, a small group of micrencephalic rats in whom the transplant tissue had failed to fill in the small brain lesions inescapably inflicted during surgery, showed greater behavioral deficits than the micrencephalic controls, suggesting that the transplant had corrected the lesion effect.     

Neocortical neuron number in humans: Effect of sex and age

Modern stereological methods provide precise and reliable estimates of the number of neurons in specific regions of the brain. We decided to estimate the total number of neocortical neurons in the normal human brain and to analyze it with respect to the major macro- and microscopical structural components, to study the internal relationships of these components, and to quantitate the influence of important physiological variables on brain structure. The 94 brains reported represent a consecutive collection of brains from the general Danish population. The average numbers of neocortical neurons were 19 billion in female brains and 23 billion in male brains, a 16% difference. In our study, which covered the age range from 20 years to 90 years, approximately 10% of all neocortical neurons are lost over the life span in both sexes. Sex and age were the main determinants of the total number of neurons in the human neocortex, whereas body size, per se, had no influence on neuron number. Some of the data presented have been analyzed by using new mathematical designs. An equation predicting the total neocortical neuron number in any individual in which sex and age are known is provided. J. Comp. Neurol. 384:312-320, 1997. © 1997 Wiley-Liss, Inc.     

Neocortical gliosis in temporal lobe epilepsy: gender-based differences

OBJECTIVE: Sex hormones can influence the timing and frequency of seizure activity. In addition, gender may influence the age of epilepsy onset and hemispheric location of focal epilepsy. Whether gender alters temporal lobe pathologies differentially is not clear. In this study, we assess if neocortical or hippocampal pathologies from patients who underwent en bloc anteriomedial temporal lobectomy (AMTR) for medically refractory epilepsy differ by gender. METHOD: Consecutive en bloc AMTR resections (n = 128), including hippocampal tissues, were systematically studied. Cortical and intracortical gliosis from a standardized location, 1.5 cm from the temporal lobe tip, was assessed for quantifiable gliotic change. Corresponding hippocampal sections were characterized according to Watson grade. These outcomes were then compared by gender. Other correlates such as age of epilepsy onset, age of risk exposure, and duration of epilepsy were similarly compared. RESULTS: Subpial and intracortical gliosis was more pronounced in women (p = 0.02, p < 0.01). Cortical thickness was reduced in women compared to men (p < 0.05). No similar gender effects were seen in Watson grade of hippocampal sclerosis or CA1-4 neuronal dropout. CONCLUSIONS: Gender may differentially influence neocortical pathologies in patients with refractory temporal lobe epilepsy. No gender effect was seen when studying hippocampal pathologies.     

Adult neurogenesis and depression: an introduction

The following essay provides a summary of a seminar given on the sixth of November, 2010 at the combined annual congress, held at Brussels of the Centro Studi Psichatrici Vrije Universiteit Brussel, Université Catholique de Louvain & the Bedfordshire Centre for Mental Health Research. The talk aimed to present a brief taster, assuming no prior knowledge, of adult neurogenesis, the formation of new nerve cells, in relation to the aetiology and treatment of depression. The talk begins with an introduction to the principles of adult neurogenesis: from initial investigations by Ramon y Cajal in the 19th century, resulting in a "static brain hypothesis", to their subsequent challenge almost one hundred years later. The potential functional implications emerging, especially in relation to depression, are explored. The fascinating effects of corticosteroids and antidepressants are used as examples to explore the possible roles of neurogenesis that have led some to propose a neurogenic theory of depression. Arguments against this theory are then presented. Finally, a consideration of future opinion: could neurogenesis be less important in the aetiology of depression, but involved in its treatment - a property of antidepressant action rather than a central final aetiological pathway. In this young branch of neuroscience controversy abounds: our understanding of the process itself, its relations and most importantly its implications are all in their infancy. This has allowed for some of the most interesting debate of recent years as to the neurological basis and treatment of affective disorders.     

Notch and neurogenesis

The Notch signaling pathway has during the last few years emerged as an important signaling mechanism for communication between neighboring cells. Many of the components in the Notch signaling pathway have been identified and the pathway is important for cellular differentiation in various organs, including the nervous system. The Notch pathway is pivotal for a process called lateral inhibition, which ensures that cells differentiate to distinct fates from an initially homogenous cell population. The aim of this review is to describe our current understanding of the molecular aspects of the Notch signaling pathway and to discuss its importance for nervous system development and disease. J. Neurosci. Res. 54:125–136, 1998. © 1998 Wiley-Liss, Inc.     

Neocortical microenvironment in patients with intractable epilepsy: potassium and chloride concentrations

PURPOSE: The regulation of extracellular ion concentrations plays an important role in neuronal function and epileptogenesis. Despite the many studies into the mechanisms of epileptogenesis in human experimental models, no data are available regarding the fluctuations of extracellular potassium ([K(+)](o)) and chloride ([Cl(-)](o)) concentrations, which could underlie seizure susceptibility in human chronically epileptic tissues in vivo. METHODS: By using cerebral microdialysis during surgical resection of epileptic foci, the basic [K(+)](o) and [Cl(-)](o) as well as their changes after epicortical electric stimulation were studied in samples of dialysates obtained from 11 patients by ion-selective microelectrodes. RESULTS: The mean basal values of [K(+)](o) and [Cl(-)](o) in all patients were 3.83 +/- 0.08 mM and 122.9 +/- 2.6 mM, respectively. However, significant differences were observed in the basal levels of both [K(+)](o) and [Cl(-)](o) between different patients. Statistically, no correlation was found between basal [K(+)](o) or [Cl(-)](o) and electrocorticogram (ECoG) spike activity, but in one patient, dramatically lowered baseline [Cl(-)](o) was accompanied by enhanced ECoG spike activity. Application of epicortical electrical stimulation increased [K(+)](o) but not [Cl(-)](o) in all cases. According to the velocity as well as spatial distribution of [K(+)](o) reduction to the prestimulation levels, three different types of responses were observed: slow decline, fast decline, and slow and fast declines at adjacent sites. CONCLUSIONS: These data may represent abnormalities in ion homeostasis of the epileptic brain.     

Neocortical asymmetry and open-field behavior in the rat

The total volume of the neocortex in each cerebral hemisphere was measured in male and female rats that had been exposed to one of two early experience treatments and subsequently tested behaviorally. Rats were either handled in infancy and raised in enriched environments or not handled in infancy and raised in standard lab cages. In adulthood they were tested in the open field for activity, for initial direction of movement out of the start box, and for laterality of wall-hugging behavior. Early experience did not have an effect on neocortical asymmetry, but a gender difference was disclosed. The right neocortex of males was larger than the left by a mean of 1.5%. Females rats did not show a significant asymmetry, although when asymmetry was present it was in favor of the left side. Cortical asymmetry correlated with openfield behavior. The degree of activity decreased with increasing neocortical asymmetry, and an interesting gender effect was present. Also, there was a positive correlation between neocortical asymmetry and direction of wall-hugging behavior, but only in animals with volume differences of less than 1%. These findings represent the first documentation of behavioral correlations with anatomic brain asymmetries in nonhuman species.     

Neocortical representational dynamics in adult primates: implications for neuropsychology

Some evidence for functional reorganization of cortical somatosensory representations in adult primates is reviewed. These examples include representation remodeling in cortical area 3b following digit amputation, digit fusion, local intracortical microstimulation, restricted cortical lesions, or as a consequence of behaviorally controlled stimulation of restricted hand surfaces. We suggest that the profound changes in the cortical representations that have been observed after these and other manipulations must bear consequences for the specific behaviors that depend on the operation of this neural machinery. Furthermore, this lifelong dynamic cortical capacity for neuronal response adaptation by use almost certainly also underlies the progressive representational remodeling that we have recorded following brain lesions.     

Neocortical death in infants: Behavioral, neurologic, and electroencephalographic characteristics

Neocortical death is a form of the persistent vegetative state characterized by the maintenance of sleep/wakeful cycles and spontaneous respirations and the lack of cognitive function. It is difficult to diagnose in neonates and young infants because their cognitive skills are limited by inexperience and by immaturity of the central nervous system. Because neocortical death has not been described previously for this age group, we report the neurologic, behavioral, electroencephalographic, and computed tomographic characteristics of three infants who survived in the persistent vegetative state following severe brain injury. Each infant appeared to exhibit some complex behaviors, including interaction with the environment and the examiners, although the electroencephalograms documented no electrical activity of cerebral origin. Computed tomography revealed extensive destruction of the cerebral hemispheres. Infants and newborns with a history suggesting brain injury and with the neurologic and behavioral characteristics described here should be evaluated with serial electroencephalograms and computed tomography to diagnose the syndrome of neocortical death.     

Neocortical temporal lobe epilepsy: intracranial EEG features and surgical outcome.

Patients with neocortical temporal lobe epilepsy (NTLE) may have less favorable outcome with anterior temporal lobectomy than those with mesial temporal foci. The authors analyzed ictal intracranial electroencephalograms (EEGs) in patients with NTLE to identify features that predict surgical outcome. The following intracranial ictal EEG features in 31 consecutive medically intractable NTLE patients were studied: Frequency (i.e., low-voltage fast [>20 Hz], recruiting ictal-onset spikes, ictal-onset rhythms less than 5 Hz, ictal-onset rhythms with repetitive sharp waves between 5 and 20 Hz); extent of ictal onset (focal, sublobar, and lobar); localization within the temporal lobe (anterior, posterior, or regional); and the time to seizure spread outside the temporal lobe (rapid, intermediate, and slow). The average follow-up period was 36.7 months (range, 18 to 60 months). Findings between two outcome groups were compared: class I group (seizure-free) and class II to IV group (persistent seizures). Twenty-one (66.7%) of 31 patients with NTLE were seizure-free. Intracranial EEG features which were significantly associated with seizure-free outcome were focal or sublobar onset, anterior temporal onset, and slow propagation time (P < 0.05). There was a trend for patients with ictal onset morphologies of slow ictal-onset rhythm and repetitive sharp waves to be seizure-free (P = 0.07). Intracranial EEG is helpful in predicting surgical outcome in NTLE patients.     

Neocortical and thalamic spread of amygdala kindled seizures

PURPOSE: Amygdala kindling is an epilepsy model involving long-term network plasticity in the nervous system. In this model, repeated weak stimulation of the amygdala eventually leads to severe motor seizures. The mechanisms for worsening behavioral seizures, and the possible role of enhanced connectivity between the amygdala and other structures have not been thoroughly investigated. METHODS: We performed simultaneous field potential recordings from the amygdala, frontal cortex, and medial thalamus during kindling in rats. Seizures were analyzed for signal power compared with baseline and for correlation between recording sites. Interictal signals were analyzed for changes in coherence between electrode contacts in kindled animals compared with sham kindled controls. RESULTS: We found that increased behavioral severity of seizures was related to increased seizure duration and to increased signal power in the frontal cortex and medial thalamus. Kindling was associated with increased connectivity between the amygdala and frontal cortex, based on increased amygdala-frontal signal correlation during seizures. In addition, during the interictal period, increased coherence was noted between amygdala and frontal contacts in kindled animals compared with controls. CONCLUSIONS: We found evidence for increased connectivity between the amygdala and frontal cortex both during seizures and in the interictal period, as a result of kindling. Enhanced connections between limbic and neocortical circuits may be important for the development of epilepsy, as well as for normal long-range network plasticity in the nervous system.     

Neocortical and limbic lesion effects on primate phonation

Five monkeys were individually trained to emit a relatively prolonged call of specified loudness in order to obtain a preferred food. At the completion of training each animal gave the required call in response to a signal cue light and withheld calls during periods in which no cue light was present.Sequential bilateral removal of the homolog of Broca's area, transitional parieto-occipital cortex, and temporal association cortex in 3 monkeys had no influence on performance of the discriminative call. There was no change in sound spectral properties of the call as a result of surgery.Bilateral removal of anterior cingulate/subcallosal gyrus in the remaining two monkeys was accompanied by loss of phonatory performance. Postoperative calls given by each of these animals in the test situation were weak and infrequent.The data indicate that control over learned, discriminative phonation in monkeys is not mediated by neorcortical regions homologous to human ‘speech’ areas.     

Neurodegeneration and neurogenesis: focus on Alzheimer's disease

Neurogenesis, or the production of new neurons from neuronal precursor cells, is a normal phenomenon in the adult brain, and is accentuated by brain injury. Forms of injury associated with increased neurogenesis include both acute (e.g., stroke) and chronic neurodegenerations. Studies on human postmortem material and transgenic mice overexpressing amyloid precursor protein mutations found in familial Alzheimer's disease (AD) suggest that AD is associated with enhanced neurogenesis. However, the mechanism responsible for this effect is unknown, as is what influence it may have on the clinical course of murine or human AD. If AD leads to the production of fully functional, mature neurons that can restore brain function, strategies aimed at further increasing endogenous neurogenesis may have therapeutic value.