Social trauma engages lateral septum circuitry to occlude social reward.

In humans, traumatic social experiences can contribute to psychiatric disorders1. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance2,3. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward4,5. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NTLS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NTLS neurons that occlude social reward processing.

Opposing relationships of childhood threat and deprivation with stria terminalis white matter.

While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress-related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post-traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms.

Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior.

The bed nucleus of the stria terminalis (BNST) is a brain region important for regulating anxiety-related behavior in both humans and rodents. Here we used a chemogenetic strategy to investigate how engagement of G protein-coupled receptor (GPCR) signaling cascades in genetically defined GABAergic BNST neurons modulates anxiety-related behavior and downstream circuit function. We saw that stimulation of vesicular γ-aminobutyric acid (GABA) transporter (VGAT)-expressing BNST neurons using hM3Dq, but neither hM4Di nor rM3Ds designer receptors exclusively activated by a designer drug (DREADD), promotes anxiety-like behavior. Further, we identified that activation of hM3Dq receptors in BNST VGAT neurons can induce a long-term depression-like state of glutamatergic synaptic transmission, indicating DREADD-induced changes in synaptic plasticity. Further, we used DREADD-assisted metabolic mapping to profile brain-wide network activity following activation of Gq-mediated signaling in BNST VGAT neurons and saw increased activity within ventral midbrain structures, including the ventral tegmental area and hindbrain structures such as the locus coeruleus and parabrachial nucleus. These results highlight that Gq-mediated signaling in BNST VGAT neurons can drive downstream network activity that correlates with anxiety-like behavior and points to the importance of identifying endogenous GPCRs within genetically defined cell populations. We next used a microfluidics approach to profile the receptorome of single BNST VGAT neurons. This approach yielded multiple Gq-coupled receptors that are associated with anxiety-like behavior and several potential novel candidates for regulation of anxiety-like behavior. From this, we identified that stimulation of the Gq-coupled receptor 5-HT2CR in the BNST is sufficient to elevate anxiety-like behavior in an acoustic startle task. Together, these results provide a novel profile of receptors within genetically defined BNST VGAT neurons that may serve as therapeutic targets for regulating anxiety states and provide a blueprint for examining how G-protein-mediated signaling in a genetically defined cell type can be used to assess behavior and brain-wide circuit function.

Long-term electrical stimulation of bed nucleus of stria terminalis for obsessive-compulsive disorder.

We previously reported that bilateral electrical stimulation in the anterior limb of the internal capsule/bed nucleus of the stria terminalis (IC/BST) effectively reduces symptoms in severe treatment-resistant obsessive-compulsive disorder (OCD) patients. Here we used a linear mixed model to investigate the evolution of symptomatic and functional status of our patients (n=24) and examined if baseline variables could predict this evolution. Data were collected during routine, clinical psychiatric visits. Our analysis showed a long-term, sustained effect of electrical stimulation in the IC/BST. After a fast initial decline of OCD symptoms, these symptoms remain relatively stable. In addition, we found a strong ON/OFF effect of stimulation (e.g., due to battery depletion). Our data also show that it is not the surgical procedure but rather the electrical stimulation that drives the improvement in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores. The Beck Depression Inventory (BDI) at baseline was the only predictor significantly related to the evolution of the Y-BOCS. A higher BDI at baseline seemed to be related to a smaller decrease of the Y-BOCS over time. In conclusion, electrical stimulation in the IC/BST has a fast and sustained effect on OCD and comorbid symptoms and functional status of patients.

CRF receptor type 2 neurons in the posterior bed nucleus of the stria terminalis critically contribute to stress recovery.

The bed nucleus of the stria terminalis (BNST) is critical in mediating states of anxiety, and its dysfunction has been linked to stress-related mental disease. Although the anxiety-related role of distinct subregions of the anterior BNST was recently reported, little is known about the contribution of the posterior BNST (pBNST) to the behavioral and neuroendocrine responses to stress. Previously, we observed abnormal expression of corticotropin-releasing factor receptor type 2 (CRFR2) to be associated with post-traumatic stress disorder (PTSD)-like symptoms. Here, we found that CRFR2-expressing neurons within the pBNST send dense inhibitory projections to other stress-related brain regions (for example, the locus coeruleus, medial amygdala and paraventricular nucleus), implicating a prominent role of these neurons in orchestrating the neuroendocrine, autonomic and behavioral response to stressful situations. Local CRFR2 activation by urocortin 3 depolarized the cells, increased the neuronal input resistance and increased firing of action potentials, indicating an enhanced excitability. Furthermore, we showed that CRFR2-expressing neurons within the pBNST are critically involved in the modulation of the behavioral and neuroendocrine response to stress. Optogenetic activation of CRFR2 neurons in the pBNST decreased anxiety, attenuated the neuroendocrine stress response, ameliorated stress-induced anxiety and impaired the fear memory for the stressful event. Moreover, activation following trauma exposure reduced the susceptibility for PTSD-like symptoms. Optogenetic inhibition of pBNST CRFR2 neurons yielded opposite effects. These data indicate the relevance of pBNST activity for adaptive stress recovery.

Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders.

The bed nucleus of the stria terminalis (BNST) is a center of integration for limbic information and valence monitoring. The BNST, sometimes referred to as the extended amygdala, is located in the basal forebrain and is a sexually dimorphic structure made up of between 12 and 18 sub-nuclei. These sub-nuclei are rich with distinct neuronal subpopulations of receptors, neurotransmitters, transporters and proteins. The BNST is important in a range of behaviors such as: the stress response, extended duration fear states and social behavior, all crucial determinants of dysfunction in human psychiatric diseases. Most research on stress and psychiatric diseases has focused on the amygdala, which regulates immediate responses to fear. However, the BNST, and not the amygdala, is the center of the psychogenic circuit from the hippocampus to the paraventricular nucleus. This circuit is important in the stimulation of the hypothalamic-pituitary-adrenal axis. Thus, the BNST has been largely overlooked with respect to its possible dysregulation in mood and anxiety disorders, social dysfunction and psychological trauma, all of which have clear gender disparities. In this review, we will look in-depth at the anatomy and projections of the BNST, and provide an overview of the current literature on the relevance of BNST dysregulation in psychiatric diseases.

Relaxin-3/RXFP3 system regulates alcohol-seeking.

Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased self-administration of alcohol in a dose-related manner and attenuated cue- and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of reward-seeking.

Different patterns of local field potentials from limbic DBS targets in patients with major depressive and obsessive compulsive disorder.

The role of distinct limbic areas in emotion regulation has been largely inferred from neuroimaging studies. Recently, the opportunity for intracranial recordings from limbic areas has arisen in patients undergoing deep brain stimulation (DBS) for neuropsychiatric disorders including major depressive disorder (MDD) and obsessive compulsive disorder (OCD). Here we test the hypothesis that distinct temporal patterns of local field potential (LFP) activity in the human limbic system reflect disease state and symptom severity in MDD and OCD patients. To this end, we recorded LFPs via implanted DBS electrodes from the bed nucleus of stria terminalis (BNST area) in 12 patients (5 OCD, 7 MDD) and from the subgenual cingulate cortex in 7 MDD patients (CG25 area). We found a distinct pattern of oscillatory activity with significantly higher α-power in MDD compared with OCD in the BNST area (broad α-band 8-14 Hz; P<0.01) and a similar level of α-activity in the CG25 area as in the BNST area in MDD patients. The mean α-power correlated with severity of depressive symptoms as assessed by the Beck depression inventory in MDD (n=14, r=0.55, P=0.042) but not with severity of obsessive compulsive symptoms in OCD. Here we show larger α-band activity in MDD patients compared with OCD recorded from intracranial DBS targets. Our results suggest that α-activity in the limbic system may be a signature of symptom severity in MDD and may serve as a potential state biomarker for closed loop DBS in MDD.

[An update on the conceptual and classification issues of anxiety, its neuroanatomy and problems of anxiolytic drug discovery]. / A szorongás konceptuális aspektusai, klasszifikációja, neuroanatómiája és az anxiolítikum-fejlesztés problémái.

Anxiety disorders are highly prevalent psychiatric diseases. In this short review we provide an overview of concepts of fear, anxiety and anxiety disorders. In addition, based on the recent literature, neuroanatomical structures involved in anxiety and functional/structural changes of these structures in anxiety disorders are also discussed. Furthemore, the pitfalls of anxiolytic drug discovery is also concerned in the paper.

Comparison of human septal nuclei MRI measurements using automated segmentation and a new manual protocol based on histology.

Septal nuclei, located in basal forebrain, are strongly connected with hippocampi and important in learning and memory, but have received limited research attention in human MRI studies. While probabilistic maps for estimating septal volume on MRI are now available, they have not been independently validated against manual tracing of MRI, typically considered the gold standard for delineating brain structures. We developed a protocol for manual tracing of the human septal region on MRI based on examination of neuroanatomical specimens. We applied this tracing protocol to T1 MRI scans (n=86) from subjects with temporal epilepsy and healthy controls to measure septal volume. To assess the inter-rater reliability of the protocol, a second tracer used the same protocol on 20 scans that were randomly selected from the 72 healthy controls. In addition to measuring septal volume, maximum septal thickness between the ventricles was measured and recorded. The same scans (n=86) were also analyzed using septal probabilistic maps and DARTEL toolbox in SPM. Results show that our manual tracing algorithm is reliable, and that septal volume measurements obtained via manual and automated methods correlate significantly with each other (p<.001). Both manual and automated methods detected significantly enlarged septal nuclei in patients with temporal lobe epilepsy in accord with a proposed compensatory neuroplastic process related to the strong connections between septal nuclei and hippocampi. Septal thickness, which was simple to measure with excellent inter-rater reliability, correlated well with both manual and automated septal volume, suggesting it could serve as an easy-to-measure surrogate for septal volume in future studies. Our results call attention to the important though understudied human septal region, confirm its enlargement in temporal lobe epilepsy, and provide a reliable new manual delineation protocol that will facilitate continued study of this critical region.

Hormonal regulation of vasotocin receptor mRNA in a seasonally breeding songbird.

Behaviors associated with breeding are seasonally modulated in a variety of species. These changes in behavior are mediated by sex steroids, levels of which likewise vary with season. The effects of androgens on behaviors associated with breeding may in turn be partly mediated by the nonapeptides vasopressin (VP) and oxytocin (OT) in mammals, and vasotocin (VT) in birds. The effects of testosterone (T) on production of these neuropeptides have been well-studied; however, the regulation of VT receptors by T is not well understood. In this study, we investigated steroid-dependent regulation of VT receptor (VTR) mRNA in a seasonally breeding songbird, the white-throated sparrow (Zonotrichia albicollis). We focused on VTR subtypes that have been most strongly implicated in social behavior: V1a and oxytocin-like receptor (OTR). Using in situ hybridization, we show that T-treatment of non-breeding males altered V1a and OTR mRNA expression in several regions associated with seasonal reproductive behaviors. For example, T-treatment increased V1a mRNA expression in the medial preoptic area, bed nucleus of the stria terminalis, and ventromedial hypothalamus. T-treatment also affected both V1a and OTR mRNA expression in nuclei of the song system; some of these effects depended on the presence or absence of a chromosomal rearrangement that affects singing behavior, plasma T, and VT immunolabeling in this species. Overall, our results strengthen evidence that VT helps mediate the behavioral effects of T in songbirds, and suggest that the chromosomal rearrangement in this species may affect the sensitivity of the VT system to seasonal changes in T.

Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2).

AIMS: Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal-executive and visuospatial dysfunctions. As the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions. METHODS: We studied pigment-Nissl-stained thick tissue sections through the cholinergic basal forebrain nuclei (that is, medial septal nucleus, nuclei of the diagonal band of Broca, basal nucleus of Meynert) of four clinically diagnosed and genetically confirmed SCA2 patients and of 13 control individuals according to the pathoanatomical approach. The pathoanatomical results were confirmed by additional quantitative investigations of these nuclei in the SCA2 patients and four age- and gender-matched controls. RESULTS: Our study revealed a severe and consistent neuronal loss in all of the cholinergic basal forebrain nuclei (medial septal nucleus: 72%; vertical nucleus of the diagonal band of Broca: 74%; horizontal limb of the diagonal band of Broca: 72%; basal nucleus of Meynert: 86%) of the SCA2 patients studied. Damage to the basal forebrain nuclei was associated with everyday relevant cognitive deficits only in our SCA2 patient with an additional Braak and Braak stage V Alzheimer's disease (AD)-related tau pathology. CONCLUSIONS: The findings of the present study: (1) indicate that the mutation and pathological process underlying SCA2 play a causative role for this severe degeneration of the cholinergic basal forebrain nuclei and (2) may suggest that degeneration of the cholinergic basal forebrain nuclei per se is not sufficient to cause profound and global dementia detrimental to everyday practice and activities of daily living.

Progressive fiber tract affections after temporal lobe surgery.

SUMMARY: Several studies reported changes in white matter architecture following temporal lobe surgery in patients with temporal lobe epilepsy (TLE) at short intervals after surgery. We investigated 20 patients with left-sided TLE using diffusion-imaging at two time points, that is, at 3-6 months and 12 months after surgery, to investigate postsurgical plasticity. We observed a loss of fiber tract integrity mainly in fiber tracts of the ipsilateral temporal lobe. Our data show that the remodeling of brain connectivity after surgical interventions continues for longer time periods. The functional implications of these plastic changes will have to be explored.

Selective degeneration of septal and hippocampal GABAergic neurons in a mouse model of amyloidosis and tauopathy.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by brain accumulation of amyloid-ß peptide and neurofibrillary tangles, which are believed to initiate a pathological cascade that results in progressive impairment of cognitive functions and eventual neuronal death. To obtain a mouse model displaying the typical AD histopathology of amyloidosis and tauopathy, we generated a triple-transgenic mouse line (TauPS2APP) by overexpressing human mutations of the amyloid precursor protein, presenilin2 and tau genes. Stereological analysis of TauPS2APP mice revealed significant neurodegeneration of GABAergic septo-hippocampal projection neurons as well as their target cells, the GABAergic hippocampal interneurons. In contrast, the cholinergic medial septum neurons remained unaffected. Moreover, the degeneration of hippocampal GABAergic interneurons was dependent on the hippocampal subfield and interneuronal subtype investigated, whereby the dentate gyrus and the NPY-positive interneurons, respectively, were most strongly affected. Neurodegeneration was also accompanied by a change in the mRNA expression of markers for inhibitory interneurons. In line with the loss of inhibitory neurons, we observed functional changes in TauPS2APP mice relative to WT mice, with strongly enhanced long-term potentiation in the medial-perforant pathway input to the dentate gyrus, and stereotypic hyperactivity. Our data indicate that inhibitory neurons are the targets of neurodegeneration in a mouse model of amyloidosis and tauopathy, thus pointing to a possible role of the inhibitory network in the pathophysiological and functional cascade of Alzheimer's disease.

A morphometric analysis of the septal nuclei in schizophrenia and affective disorders: reduced neuronal density in the lateral septal nucleus in bipolar disorder.

The septal nuclei are assumed to play a significant role in the pathophysiology of schizophrenia and affective disorders. The aim of this study was to morphometrically characterize the septal nuclei in patients with schizophrenia, bipolar disorder, and major depressive disorder, when compared with healthy control subjects. We analyzed the septal nuclei by determining the density and size of the neurons in postmortem brains in 17 patients with schizophrenia, 8 patients with bipolar disorder, 7 patients with major depressive disorder, and 14 control subjects matched for age and gender. There was a significant reduction in the neuronal density, but not in the mean cross-sectional area, in the lateral septal nucleus (P = 0.013) in patients with bipolar disorder when compared with control subjects. There were no significant changes in the neuronal density of the septal nuclei of the medial and lateral cell groups in patients with schizophrenia and major depressive disorder when compared with control subjects. There was a significant negative correlation between neuronal density in the lateral septal nucleus and disease duration in patients with major depressive disorder (P = 0.037, r = -0.9). The histopathological abnormality of the decreased neuronal density in the lateral septal nucleus, which is an important limbic region involved in emotions, might be a neuropathological correlate of bipolar disorder.

The paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice.

Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNSTCRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNSTCRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNSTCRF neurons, and this polysynaptic PVTVGLUT2-BNSTCRF circuit is more robust in females than males. Chemogenetic inhibition of the PVTBNST projection promoted binge alcohol drinking only in female mice, while activation reduced avoidance behavior in both sexes. Lastly, repeated binge drinking produced a female-like phenotype in the male PVT-BNSTCRF excitatory synapse without altering the function of PVTBNST neurons per se. Our data describe a complex, feedforward inhibitory PVTVGLUT2-BNSTCRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.

Medial septum tau accumulation induces spatial memory deficit via disrupting medial septum-hippocampus cholinergic pathway.

Tau accumulation and cholinergic impairment are characteristic pathologies in Alzheimer's disease (AD). However, the causal role of tau accumulation in cholinergic lesion is elusive. Here, we observed an aberrant tau accumulation in the medial septum (MS) of 3xTg and 5xFAD mice, especially in their cholinergic neurons. Overexpressing hTau in mouse MS (MShTau ) for 6 months but not 3 months induced spatial memory impairment without changing object recognition and anxiety-like behavior, indicating a specific and time-dependent effect of MS-hTau accumulation on spatial cognitive functions. With increasing hTau accumulation, the MShTau mice showed a time-dependent cholinergic neuron loss with reduced cholinergic projections to the hippocampus. Intraperitoneal administration of donepezil, a cholinesterase inhibitor, for 1 month ameliorated the MS-hTau-induced spatial memory deficits with preservation of MS-hippocampal cholinergic pathway and removal of tau load; and the beneficial effects of donepezil was more prominent at low dose. Proteomics revealed that MS-hTau accumulation deregulated multiple signaling pathways with numerous differentially expressed proteins (DEPs). Among them, the vacuolar protein sorting-associated protein 37D (VP37D), an autophagy-related protein, was significantly reduced in MShTau mice; the reduction of VP37D was restored by donepezil, and the effect was more significant at low dose than high dose. These novel evidences reveal a causal role of tau accumulation in linking MS cholinergic lesion to hippocampus-dependent spatial cognitive damages as seen in the AD patients, and the new tau-removal and autophagy-promoting effects of donepezil may extend its application beyond simple symptom amelioration to potential disease modification.

Neurokinin receptor mechanisms in forebrain medial septum modulate nociception in the formalin model of inflammatory pain.

The present study has explored the hypothesis that neurokinin1 receptors (NK1Rs) in medial septum (MS) modulate nociception evoked on hind paw injection of formalin. Indeed, the NK1Rs in MS are localized on cholinergic neurons which have been implicated in nociception. In anaesthetized rat, microinjection of L-733,060, an antagonist at NK1Rs, into MS antagonized the suppression of CA1 population spike (PS) evoked on peripheral injection of formalin or on intraseptal microinjection of substance P (SP), an agonist at NK1Rs. The CA1 PS reflects the synaptic excitability of pyramidal cells in the region. Furthermore, microinjection of L-733,060 into MS, but not LS, attenuated formalin-induced theta activation in both anaesthetized and awake rat, where theta reflects an oscillatory information processing by hippocampal neurons. The effects of L-733,060 on microinjection into MS were nociceptive selective as the antagonist did not block septo-hippocampal response to direct MS stimulation by the cholinergic receptor agonist, carbachol, in anaesthetized animal or on exploration in awake animal. Interestingly, microinjection of L-733,060 into both MS and LS attenuated formalin-induced nociceptive flinches. Collectively, the foregoing novel findings highlight that transmission at NK1R provide an affective valence to septo-hippocampal information processing and that peptidergic transmission in the septum modulates nociceptive behaviours.

Effects of Prolonged Seizures on Basal Forebrain Cholinergic Neurons: Evidence and Potential Clinical Relevance.

Seizures originating from limbic structures, especially when prolonged for several minutes/hours up to status epilepticus (SE), can cause specific neurodegenerative phenomena in limbic and subcortical structures. The cholinergic nuclei belonging to the basal forebrain (BF) (namely, medial septal nucleus (MSN), diagonal band of Broca (DBB), and nucleus basalis of Meynert (NBM)) belong to the limbic system, while playing a pivotal role in cognition and sleep-waking cycle. Given the strong interconnections linking these limbic nuclei with limbic cortical structures, a persistent effect of SE originating from limbic structures on cBF morphology is plausible. Nonetheless, only a few experimental studies have addressed this issue. In this review, we describe available data and discuss their significance in the scenario of seizure-induced brain damage. In detail, the manuscript moves from a recent study in a model of focally induced limbic SE, in which the pure effects of seizure spreading through the natural anatomical pathways towards the cholinergic nuclei of BF were tracked by neuronal degeneration. In this experimental setting, a loss of cholinergic neurons was measured in all BF nuclei, to various extents depending on the specific nucleus. These findings are discussed in the light of the effects on the very same nuclei following SE induced by systemic injections of kainate or pilocarpine. The various effects including discrepancies among different studies are discussed. Potential implications for human diseases are included.

DTI of commissural fibers in patients with Chiari II-malformation.

Chiari II-malformation is a complex congenital deformity of the brain which is frequently associated with hydrocephalus. Abnormalities of the corpus callosum are known to occur in the majority of patients. The objective of the present study was to study the microstructure of the corpus callosum (CC) and the anterior commissure (AC) to differentiate between different mechanisms of damage to these structures. We investigated 6 patients with Chiari II-malformation and 6 well-matched healthy volunteers employing T1-weighted 3D imaging and diffusion tensor imaging (DTI) to determine the fractional anisotropy (FA) and cross-sectional area of the CC and AC, as well as with neuropsychological testing. Four patients showed hydrocephalus, two patients had callosal dysplasia and four had a hypoplastic CC. The callosal FA in the patients was significantly reduced which was less pronounced for the genu alone. The area of CC was also reduced in Chiari II-patients. There was a strong correlation between the size and FA of the CC in the patients. In contrast, the thickness of the AC was significantly increased and was associated with higher FA in the patients. In psychological tests all patients showed reduced verbal memory; all but one patient showed reduced IQ as well as impaired visuo-spatial performance, indicating deficits in tasks requiring parieto-occipital integration. The existence of callosal dysplasia in two patients, the diminished FA reduction in the genu and the correlation of the cross-sectional area and FA in the patients point to a developmental white matter damage beside that exerted by hydrocephalus alone.