Understanding the effect of cognitive/brain reserve and depression on regional atrophy in early Alzheimer’s disease

Introduction: Depression in patients with mild cognitive impairment (MCI) and dementia of the Alzheimer’s type (AD) is associated with worse prognosis. Indeed, depressed MCI patients have worse cognitive performance and greater loss of gray-matter volume in several brain areas. To date, knowledge of the factors that can mitigate this detrimental effect is still limited. The aim of the present study was to understand in what way cognitive reserve/brain reserve and depression interact and are linked to regional atrophy in early stage AD. Methods: Depression was evaluated with the Patient Health Questionnaire-9 in 90 patients with early AD, and a cutoff of ≥ 5 was used to separate depressed (n = 44) from non-depressed (n = 46) patients. Each group was further stratified into high/low cognitive reserve/brain reserve. Cognitive reserve was calculated using years of education as proxy, while normalized parenchymal volumes were used to estimate brain reserve. Voxel-based morphometry was carried out to extract and analyze gray-matter maps. 2 × 2 ANCOVAs were run to test the effect of the reserve-by-depression interaction on gray matter. Age and hippocampal ratio were used as covariates. Composite indices of major cognitive domains were also analyzed with comparable models. Results: No reserve-by-depression interaction was found in the analytical models of gray matter. Depression was associated with less gray matter volume in the cerebellum and parahippocampal gyrus. The brain reserve-by-depression interaction was a significant predictor of executive functioning. Among those with high brain reserve, depressed patients had poorer executive skills. No significant results were found in association with cognitive reserve. Conclusion: These findings suggest that brain reserve may modulate the association between neurodegeneration and depression in patients with MCI and dementia of the AD type, influencing in particular executive functioning

A combinatory genetic strategy for targeting neurogliaform neurons in the mouse basolateral amygdala

The mouse basolateral amygdala (BLA) contains various GABAergic interneuron subpopulations, which have distinctive roles in the neuronal microcircuit controlling numerous behavioral functions. In mice, roughly 15% of the BLA GABAergic interneurons express neuropeptide Y (NPY), a reasonably characteristic marker for neurogliaform cells (NGFCs) in cortical-like brain structures. However, genetically labeled putative NPY-expressing interneurons in the BLA yield a mixture of interneuron subtypes besides NGFCs. Thus, selective molecular markers are lacking for genetically accessing NGFCs in the BLA. Here, we validated the NGFC-specific labeling with a molecular marker, neuron-derived neurotrophic factor (NDNF), in the mouse BLA, as such specificity has been demonstrated in the neocortex and hippocampus. We characterized genetically defined NDNF-expressing (NDNF+) GABAergic interneurons in the mouse BLA by combining the Ndnf-IRES2-dgCre-D transgenic mouse line with viral labeling, immunohistochemical staining, and in vitro electrophysiology. We found that BLA NDNF+ GABAergic cells mainly expressed NGFC neurochemical markers NPY and reelin (Reln) and exhibited small round soma and dense axonal arborization. Whole-cell patch clamp recordings indicated that most NDNF+ interneurons showed late spiking and moderate firing adaptation. Moreover, ∼81% of BLA NDNF+ cells generated retroaxonal action potential after current injections or optogenetic stimulations, frequently developing into persistent barrage firing. Optogenetic activation of the BLA NDNF+ cell population yielded both GABAA- and GABAB receptor-mediated currents onto BLA pyramidal neurons (PNs). We demonstrate a combinatory strategy combining the NDNF-cre mouse line with viral transfection to specifically target adult mouse BLA NGFCs and further explore their functional and behavioral roles

Basic properties of nonsmooth Hormander's vector fields and Poincare's inequality

We consider a family of vector fields defined in some bounded domain of R^p, and we assume that they satisfy Hormander's rank condition of some step r, and that their coefficients have r-1 continuous derivatives. We extend to this nonsmooth context some results which are well-known for smooth Hormander's vector fields, namely: some basic properties of the distance induced by the vector fields, the doubling condition, Chow's connectivity theorem, and, under the stronger assumption that the coefficients belong to C^{r-1,1}, Poincare's inequality. By known results, these facts also imply a Sobolev embedding. All these tools allow to draw some consequences about second order differential operators modeled on these nonsmooth Hormander's vector fields.Comment: 60 pages, LaTeX; Section 6 added and Section 7 (6 in the previous version) changed. Some references adde

Non-Hebbian plasticity transforms transient experiences into lasting memories

Publisher Copyright: © 2023, Faress et al.The dominant models of learning and memory, such as Hebbian plasticity, propose that experiences are transformed into memories through input-specific synaptic plasticity at the time of learning. However, synaptic plasticity is neither strictly input-specific nor restricted to the time of its induction. The impact of such forms of non-Hebbian plasticity on memory has been difficult to test, and hence poorly understood. Here, we demonstrate that synaptic manipulations can deviate from the Hebbian model of learning, yet produce a lasting memory. First, we established a weak associative conditioning protocol in mice, where optogenetic stimulation of sensory thalamic input to the amygdala was paired with a footshock, but no detectable memory was formed. However, when the same input was potentiated minutes before or after, or even 24 hr later, the associative experience was converted into a lasting memory. Importantly, potentiating an independent input to the amygdala minutes but not 24 hr after the pairing produced a lasting memory. Thus, our findings suggest that the process of transformation of a transient experience into a memory is neither restricted to the time of the experience nor to the synapses triggered by it; instead, it can be influenced by past and future events.publishersversionpublishe

Differential Modulation of Excitatory and Inhibitory Striatal Synaptic Transmission by Histamine

Information processing in the striatum is critical for basal ganglia function and strongly influenced by neuromodulators (e.g., dopamine). The striatum also receives modulatory afferents from the histaminergic neurons in the hypothalamus which exhibit a distinct diurnal rhythm with high activity during wakefulness, and little or no activity during sleep. In view of the fact that the striatum also expresses a high density of histamine receptors, we hypothesized that released histamine will affect striatal function. We studied the role of histamine on striatal microcircuit function by performing whole-cell patch-clamp recordings of neurochemically identified striatal neurons combined with electrical and optogenetic stimulation of striatal afferents in mouse brain slices. Bath applied histamine had many effects on striatal microcircuits. Histamine, acting at H(2) receptors, depolarized both the direct and indirect pathway medium spiny projection neurons (MSNs). Excitatory, glutamatergic input to both classes of MSNs from both the cortex and thalamus was negatively modulated by histamine acting at presynaptic H(3) receptors. The dynamics of thalamostriatal, but not corticostriatal, synapses were modulated by histamine leading to a facilitation of thalamic input. Furthermore, local inhibitory input to both classes of MSNs was negatively modulated by histamine. Subsequent dual whole-cell patch-clamp recordings of connected pairs of striatal neurons revealed that only lateral inhibition between MSNs is negatively modulated, whereas feedforward inhibition from fast-spiking GABAergic interneurons onto MSNs is unaffected by histamine. These findings suggest that the diurnal rhythm of histamine release entrains striatal function which, during wakefulness, is dominated by feedforward inhibition and a suppression of excitatory drive

A New Case of Prenatally Diagnosed Pentasomy X: Review of the Literature

Pentasomy X is a rare chromosomal abnormality probably due to a nondisjunction during the meiosis. Only four cases prenatally diagnosed were described until now. Our case is the fifth one prenatally diagnosed at 20 weeks of gestational age in a 39-years-old woman. She underwent invasive prenatal diagnosis for her advanced maternal age without any other known risk factor. Amniocentesis performed at 17 weeks showed a female 49, XXXXX karyotype. The ultrasonographic examination revealed nonspecific signs of a mild early fetal growth retardation and no significant increased nuchal fold. The fetal autopsy and the X-ray excluded major malformations. Prenatal diagnosis is often difficult due to the lack of indicative ultrasonographic findings and the rarity of described cases. The influence of the mother’s age on the occurrence of penta-X syndrome has not been determined. Considering the lack of correlation between advanced maternal age and increased risk for pentasomy X, as well as the absence of typical echographic signs, evaluation of the inclusion of a noninvasive prenatal test (NIPT) that expands clinical coverage to include the X and Y chromosomes in routine prenatal diagnosis should be considered as well as three-dimensional ultrasound to detect any helpful indicative prognostic signs

Case Report A New Case of Prenatally Diagnosed Pentasomy X: Review of the Literature

Pentasomy X is a rare chromosomal abnormality probably due to a nondisjunction during the meiosis. Only four cases prenatally diagnosed were described until now. Our case is the fifth one prenatally diagnosed at 20 weeks of gestational age in a 39-yearsold woman. She underwent invasive prenatal diagnosis for her advanced maternal age without any other known risk factor. Amniocentesis performed at 17 weeks showed a female 49, XXXXX karyotype. The ultrasonographic examination revealed nonspecific signs of a mild early fetal growth retardation and no significant increased nuchal fold. The fetal autopsy and the Xray excluded major malformations. Prenatal diagnosis is often difficult due to the lack of indicative ultrasonographic findings and the rarity of described cases. The influence of the mother's age on the occurrence of penta-X syndrome has not been determined. Considering the lack of correlation between advanced maternal age and increased risk for pentasomy X, as well as the absence of typical echographic signs, evaluation of the inclusion of a noninvasive prenatal test (NIPT) that expands clinical coverage to include the X and Y chromosomes in routine prenatal diagnosis should be considered as well as three-dimensional ultrasound to detect any helpful indicative prognostic signs

Potential theory results for a class of PDOs admitting a global fundamental solution

We outline several results of Potential Theory for a class of linear par-tial differential operators L of the second order in divergence form. Under essentially the sole assumption of hypoellipticity, we present a non-invariant homogeneous Harnack inequality for L; under different geometrical assumptions on L (mainly, under global doubling/Poincar\ue9 assumptions), it is described how to obtainan invariant, non-homogeneous Harnack inequality. When L is equipped with a global fundamental solution \u393, further Potential Theory results are available (such as the Strong Maximum Principle). We present some assumptions on L ensuring that such a \u393 exists

Oscillatory Substrates of Fear and Safety

Oscillatory activity in the basolateral amygdala (BLA) is critical for emotional behavior. In this issue of Neuron, Stujenske et al. (2014) describe novel dynamics of BLA theta-gamma-coupled neuronal oscillations associated with conditioned and innate fear