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Functional connectivity is a neurobiological notion, informally stating that there would be a strong dependence between neurons and that this dependence might be useful in understanding the way the brain encodes stimuli, programs actions, etc. However, in practice such strong dependencies are often reconstructed via Hawkes processes based on an amazingly small number of neurons, because of the very scarce observation of this very complex and huge network. We derive new simple equations, which explain how the ideal Hawkes reconstruction is linked to the covariance between the observed neurons. These equations help us in particular to understand what the Hawkes reconstruction does in two settings, synchronization and classical point process asymptotics. Moreover they might help us to also understand what is qualitatively happening at the scale of the huge unobserved network, paving the path for a possible mathematical definition of functional connectivity.

Background: Apathy and depression are two early behavioral symptoms in Alzheimer's disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology. Objective: The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion. Methods: Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort. Results: Among individuals with SCD (n = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time. Conclusion: Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely—compared to depression—to be associated with conversion to dementia. [ABSTRACT FROM AUTHOR]

The habenulo-interpeduncular system (HIPS) is now recognized as a critical circuit modulating aversion, reward, and social behavior. There is evidence that dysfunction of this circuit leads to psychiatric disorders. Because psychiatric diseases may originate in developmental abnormalities, it is crucial to investigate the developmental mechanisms controlling the formation of the HIPS. Thus far, this issue has been the focus of limited studies. Here, we explored the developmental processes underlying the formation of the medial habenula (MHb) and its unique output, the interpeduncular nucleus (IPN), in mice independently of their gender. We report that the Otx2 homeobox gene is essential for the proper development of both structures. We show that MHb and IPN neurons require Otx2 at different developmental stages and, in both cases, Otx2 deletion leads to disruption of HIPS subcircuits. Finally, we show that Otx2 + neurons tend to be preferentially interconnected. This study reveals that synaptically connected components of the HIPS, despite radically different developmental strategies, share high sensitivity to Otx2 expression. [ABSTRACT FROM AUTHOR]

The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by the elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis, circadian rhythm, and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by subchronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, whereas LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset. [ABSTRACT FROM AUTHOR]

Three experiments investigated the role in memory processing of dopamine (DA) afferents to the hippocampus (HPC) that arise from the ventral tegmental area. One hypothesis is that D1/D5 receptor activation in HPC is necessary for the encoding of novel, episodic-like information; the other is thatDAactivation ensures the greater temporal persistence of transient hippocampal memory traces. Rats (n=35) were trained, in separate experiments using an episodic-like memory task, to learn six paired associates (PAs) in an "event arena" involving a repeated association between specific flavors of food and locations in space. After 6 weeks of training, rats had learned a "schema" such that two new paired associates could be acquired in a single trial in one session (episodic-like memory). We show that encoding of novel PAs is sensitive to intra hippocampal microinfusion of the NMDA antagonist D-AP-5. Experiment 1 established that intrahippocampal infusion of the D1/D5 dopaminergic antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrochloride] before encoding of new PAs caused impaired memory 24 h later but that SCH23390 had no effect on the later memory of previously established PAs. Experiment 2 established that SCH23390 modulated the persistence of new memories over time (30 min vs 24 h) rather than affecting initial encoding. Experiment 3 revealed that the impact of SCH23390 was not mediated by state dependence nor had an effect on memory retrieval. These findings support the second hypothesis and establish that persistent, long-term memory of rapid, hippocampal-mediated acquisition of new paired associates requires activation of D1/D5 receptors in HPC at or around the time of encoding. [ABSTRACT FROM AUTHOR]

Interferon-α (IFN-α) is used clinically in the treatment of several pathologies such as hepatitis C and various cancers. The positive therapeutic potential is however often limited by negative secondary effects which include major depression, one of the cardinal symptoms of which is anhedonia which has been operationalised as a decreased sensitivity to rewards (inability to experience pleasure). Previous studies have demonstrated the existence of anhedonia in rats following an acute injection of IFN-α at doses corresponding to those used in clinical applications. If this previously demonstrated anhedonia is indeed part of a depression syndrome in rats, this behavioural symptom should be reversible by the administration of antidepressants. The objective of the present experiment was to determine whether two commonly used antidepressants (desipramine and fluoxetine) were effective in ameliorating IFN-α-induced anhedonia in rats. The experiment consisted of two phases. In the first, the effects of daily systemic injections of 104 units/kg of IFN-α (or vehicle) were evaluated with the three-bottle (1%, 8%, and 32%) sucrose-consumption test. In the second phase of the experiment, in addition to continued injections of IFN-α, different groups received daily injections of desipramine (7.5 mg/kg ip), fluoxetine (7.5 mg/kg ip), or vehicle. The IFN-α injections during Phase 1 resulted in clear anhedonia, as expressed by increased consumption of the 32% solution and decreased consumption of 1% over the 33 days of this phase. After 15 days of antidepressant treatments, 32% sucrose consumption returned to baseline values. We have therefore confirmed that IFN-α-induced anhedonia is susceptible to reversal following chronic antidepressant treatment and thus it may appear timely to consider the prophylactic use of such in particular patients prescribed IFN in the clinic. [Copyright &y& Elsevier]

There is a growing consensus that Alzheimer's disease (AD) involves failure of the homeostatic machinery, which underlies the firing stability of neural circuits. What are the culprits leading to neuron firing instability? The amyloid precursor protein (APP) is central to AD pathogenesis, and we recently showed that its intracellular domain (AICD) could modify synaptic signal integration. We now hypothesize that AICD modifies neuron firing activity, thus contributing to the disruption of memory processes. Using cellular, electrophysiological, and behavioral techniques, we show that pathological AICD levels weaken CA1 neuron firing activity through a gene-transcription-dependent mechanism. Furthermore, increased AICD production in hippocampal neurons modifies oscillatory activity, specifically in the γ-frequency range, and disrupts spatial memory task. Collectively, our data suggest that AICD pathological levels, observed in AD mouse models and in human patients, might contribute to progressive neuron homeostatic failure, driving the shift from normal aging to AD. • Increasing AICD levels weakens neuron firing activity in CA1 pyramidal neurons • This alteration is due to modified Ca2+ and K+ channels conductances • Modeling this alteration predicts a specific impact on hippocampal gamma oscillations • Increasing hippocampal AICD levels weakens gamma-oscillation-dependent spatial memory Pousinha et al. report that increased AICD levels, a peptide representing amyloid precursor protein (APP) C-terminal domain, render CA1 pyramidal neurons hypoexcitable by altering Ca+ and K+ channel conductances. Modeling this alteration predicts decreased gamma oscillations. They show that increasing AICD levels in vivo weakens gamma-oscillation-dependent spatial memory. [ABSTRACT FROM AUTHOR]

An abstract of the article "Early hippocampal synaptic plasticity and episodic like-memory deficits in a transgenic mouse model of Alzheimer disease - involvement of corticosterone" by Fabien Lanté, Magda Chafai, Elisabeth Raymond and colleagues is presented.

Abstract SCN1A (Na V 1.1 sodium channel) mutations cause Dravet syndrome (DS) and GEFS+ (which is in general milder), and are risk factors in other epilepsies. Phenotypic variability limits precision medicine in epilepsy, and it is important to identify factors that set phenotype severity and their mechanisms. It is not yet clear whether SCN1A mutations are necessary for the development of severe phenotypes or just for promoting seizures. A relevant example is the pleiotropic R1648H mutation that can cause either mild GEFS+ or severe DS. We used a R1648H knock-in mouse model (Scn1a RH/+) with mild/asymptomatic phenotype to dissociate the effects of seizures and of the mutation per se. The induction of short repeated seizures, at the age of disease onset for Scn1a mouse models (P21), had no effect in WT mice, but transformed the mild/asymptomatic phenotype of Scn1a RH/+ mice into a severe DS-like phenotype, including frequent spontaneous seizures and cognitive/behavioral deficits. In these mice, we found no major modifications in cytoarchitecture or neuronal death, but increased excitability of hippocampal granule cells, consistent with a pathological remodeling. Therefore, we demonstrate for our model that an SCN1A mutation is a prerequisite for a long term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se , may increase the risk of second hits to develop severe phenotypes. Highlights • The interaction between seizures and the Scn1a mutation causes severe phenotypes. • Remodeling underlying phenotype worsening is not directly linked to mutation's effect. • Genetic variants may increase the risk of second hits to worsen phenotypes. [ABSTRACT FROM AUTHOR]

Amyloid-β is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-β (Aβο) is now believed to represent the main Amyloid-β species affecting synapse function. Yet, the exact molecular mechanism by which Aβο modifies synapse function remains to be fully elucidated. There is accumulating evidence that glucocorticoid receptors (GRs) might participate in Aβο generation and activity in the brain. Here, we provide evidence for an acute functional cross-talk between Aβ and GRs at hippocampal excitatory synapses. Using live imaging and biochemical analysis of post-synaptic densities (PSD) in cultured hippocampal neurons, we show that synthetic Aβo (100 nM) increases GR levels in spines and PSD. Also, in these cultured neurons, blocking GRs with two different GR antagonists prevents Aβo-mediated PSD95 increase within the PSD. By analyzing long-term potentiation (LTP) and long-term depression (LTD) in ex vivo hippocampal slices after pharmacologically blocking GR, we also show that GR signaling is necessary for Aβo-mediated LTP impairment, but not Aβo-mediated LTD induction. The necessity of neuronal GRs for Aβo-mediated LTP was confirmed by genetically removing GRs in vivo from CA1 neurons using conditional GR mutant mice. These results indicate a tight functional interplay between GR and Aβ activities at excitatory synapses. [ABSTRACT FROM AUTHOR]

The rat dorsomedial (DMS) and dorsolateral striatum (DLS), equivalent to caudate nucleus and putamen in primates, are required for goal-directed and habit behaviour, respectively. However, it is still unclear whether and how this functional dichotomy emerges in the course of learning. In this study we investigated this issue by recording DMS and DLS single neuron activity in rats performing a continuous spatial alternation task, from the acquisition to optimized performance. We first applied a classical analytical approach to identify task-related activity based on the modifications of single neuron firing rate in relation to specific task events or maze trajectories. We then used an innovative approach based on Hawkes process to reconstruct a directed connectivity graph of simultaneously recorded neurons, that was used to decode animal behavior. This approach enabled us to better unravel the role of DMS and DLS neural networks across learning stages. We showed that DMS and DLS display different task-related activity throughout learning stages, and the proportion of coding neurons over time decreases in the DMS and increases in the DLS. Despite theses major differences, the decoding power of both networks increases during learning. These results suggest that DMS and DLS neural networks gradually reorganize in different ways in order to progressively increase their control over the behavioral performance. Significance statement Our study helps understanding the role of the dorsomedial (DMS) and dorsolateral striatum (DLS) during the acquisition and optimization of a behavioral strategy. It is generally believed that the DMS mediates action-outcome associations, whereas the DLS supports habit behavior, but it is still unclear how these processes emerges during learning. To analyze the dynamic changes of DMS and DLS network activity across learning stages, we used a mathematical analysis combining single neuron firing rate and connectivity between neurons to decode rat behavior in a goal-directed spatial task. We demonstrated that both DMS and DLS activity supports behavioral performance throughout all learning stages, thus challenging the hypothesis of a gradual shift from DMS to DLS activity., (Copyright © 2024 Villet et al.)

The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer's disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in vivo AICD expression, ex vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GluN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism. We further show that AICD increase in mature neurons, as reported in AD, alters synaptic NMDAR composition to an immature-like GluN2B-rich profile. This disrupts synaptic signal integration, via over-activation of SK channels, and synapse plasticity, phenotypes rescued by GluN2B antagonism. We provide a new physiological role for AICD, which becomes pathological upon AICD increase in mature neurons. Thus, AICD could contribute to AD synaptic failure.

Several recent reports based on microdialysis have shown that repeated injections of IFN-alpha induce reduced dopamine (DA) activity in the rodent brain, and specifically within the striatum. This mesolimbic DA system is thought to play a central role in controlling latent inhibition (LI), which refers to the phenomenon in which conditioning proceeds more slowly to an irrelevant pre-exposed (PE) stimulus. The purpose of the present experiment was to evaluate whether chronic treatment with IFN-alpha may induce similar effects on LI as other DA-depleting manipulations. Rats were injected daily, for 24 days either with 10(4)IU IFN-alpha or vehicle, while monitoring their locomotor activity in photocell cages. No changes in locomotor activity, either during the acute period after the first injection, or progressively over the chronic period were observed. LI was then evaluated in these rats with a Conditioned Taste Aversion (CTA) paradigm. Half of each group of rats were pre-exposed to the 5% sucrose Conditioned Stimulus (CS) for 30 min on three successive days before the conditioning session in which the 30 min access to the 5% sucrose solution was followed by a 0.15M injection of 127 mg/kg LiCl. Two test sessions, in which rats were given a choice between the 5% sucrose solution and water, were given 48 and 72 h after the conditioning session. The results showed moderate LI in the control group, which was considerably potentiated in the IFN-alpha group despite the absence of any change in locomotor activity. These results are interpreted as providing indirect support for the theory that suggests that LI depends on DA activity in the nucleus accumbens (NAcc).