Ventral tegmental area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning.

In most models of neuronal plasticity and memory, dopamine is thought to promote the long-term maintenance of Long-Term Potentiation (LTP) underlying memory processes, but not the initiation of plasticity or new information storage. Here, we used optogenetic manipulation of midbrain dopamine neurons in male DAT::Cre mice, and discovered that stimulating the Schaffer collaterals - the glutamatergic axons connecting CA3 and CA1 regions - of the dorsal hippocampus concomitantly with midbrain dopamine terminals within a 200 millisecond time-window triggers LTP at glutamatergic synapses. Moreover, we showed that the stimulation of this dopaminergic pathway facilitates contextual learning in awake behaving mice, while its inhibition hinders it.

No major effect of dopamine receptor 1/5 antagonist SCH-23390 on epileptic activity in the Tg2576 mouse model of amyloidosis.

The excitation-inhibition imbalance manifesting as epileptic activities in Alzheimer's disease is gaining more and more attention, and several potentially involved cellular and molecular pathways are currently under investigation. Based on in vitro studies, dopamine D1-type receptors in the anterior cingulate cortex and the hippocampus have been proposed to participate in this peculiar co-morbidity in mouse models of amyloidosis. Here, we tested the implication of dopaminergic transmission in vivo in the Tg2576 mouse model of Alzheimer's disease by monitoring epileptic activities via intracranial EEG before and after treatment with dopamine antagonists.

Enriched environmental exposure reduces the onset of action of the serotonin norepinephrin reuptake inhibitor venlafaxine through its effect on parvalbumin interneurons plasticity in mice.

Mood disorders are associated with hypothalamic-pituitary-adrenal axis overactivity resulting from a decreased inhibitory feedback exerted by the hippocampus on this brain structure. Growing evidence suggests that antidepressants would regulate hippocampal excitatory/inhibitory balance to restore an effective inhibition on this stress axis. While these pharmacological compounds produce beneficial clinical effects, they also have limitations including their long delay of action.

Neuronal hyperexcitability in the Tg2576 mouse model of Alzheimer's disease - the influence of sleep and noradrenergic transmission.

The link between Alzheimer's disease (AD) and network hypersynchrony - manifesting as epileptic activities - received considerable attention in the past decade. However, several questions remain unanswered as to its mechanistic underpinnings. Therefore, our objectives were (1) to better characterise epileptic events in the Tg2576 mouse model throughout the sleep-wake cycle and disease progression via electrophysiological recordings and (2) to explore the involvement of noradrenergic transmission in this pathological hypersynchrony.

Sequential inhibitory plasticities in hippocampal area CA2 and social memory formation.

Area CA2 is a critical region for diverse hippocampal functions including social recognition memory. This region has unique properties and connectivity. Notably, intra-hippocampal excitatory inputs to CA2 lack canonical long-term plasticity, but inhibitory transmission expresses a long-term depression mediated by Delta-opioid receptors (DOR-iLTDs).

Altered inhibitory function in hippocampal CA2 contributes in social memory deficits in Alzheimer's mouse model.

Parvalbumin (PV)-expressing interneurons which are often associated with the specific extracellular matrix perineuronal net (PNN) play a critical role in the alteration of brain activity and memory performance in Alzheimer's disease (AD). The integrity of these neurons is crucial for normal functioning of the hippocampal subfield CA2, and hence, social memory formation. Here, we find that social memory deficits of mouse models of AD are associated with decreased presence of PNN around PV cells and long-term synaptic plasticity in area CA2.

Maturation of PNN and ErbB4 Signaling in Area CA2 during Adolescence Underlies the Emergence of PV Interneuron Plasticity and Social Memory.

Adolescence is a vulnerable period characterized by major cognitive changes. The mechanisms underlying the emergence of new cognitive functions are poorly understood. We find that a long-term depression of inhibitory transmission (iLTD) from parvalbumin-expressing (PV+) interneurons in the hippocampal area Cornu Ammonis 2 (CA2) is absent in young mice but emerges at the end of adolescence.

Ovarian Cycle Stages Modulate Alzheimer-Related Cognitive and Brain Network Alterations in Female Mice.

Alzheimer's disease (AD) begins several decades before the onset of clinical symptoms, at a time when women may still undergo reproductive cycling. Whether ovarian functions alter substrates of AD pathogenesis is unknown. Here we show that ovarian cycle stages significantly modulate AD-related alterations in neural network patterns, cognitive impairments, and pathogenic protein production in the hAPP-J20 mouse model of AD.

Early disruption of parvalbumin expression and perineuronal nets in the hippocampus of the Tg2576 mouse model of Alzheimer's disease can be rescued by enriched environment.

Recent findings show that parvalbumin (PV) interneuron function is impaired in Alzheimer's disease (AD), and that this impairment in PV function can be linked to network dysfunction and memory deficits. PV cells are often associated with a specific extracellular matrix, the perineuronal net (PNN). PNNs are believed to protect PV cell integrity, and whether the amyloidopathy affects PNNs remains unclear.

Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease.

Inhibitory interneurons regulate the oscillatory rhythms and network synchrony that are required for cognitive functions and disrupted in Alzheimer's disease (AD). Network dysrhythmias in AD and multiple neuropsychiatric disorders are associated with hypofunction of Nav1.1, a voltage-gated sodium channel subunit predominantly expressed in interneurons.

Network dysfunction in α-synuclein transgenic mice and human Lewy body dementia.

Objective: Dementia with Lewy bodies (DLB) is associated with the accumulation of wild-type human α-synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN.

Methods: To determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity-dependent gene products in SYN transgenic mice.

Environmental enrichment does not influence hypersynchronous network activity in the Tg2576 mouse model of Alzheimer's disease.

The cognitive reserve hypothesis claims that the brain can overcome pathology by reinforcing preexistent processes or by developing alternative cognitive strategies. Epidemiological studies have revealed that this reserve can be built throughout life experiences as education or leisure activities. We previously showed that an early transient environmental enrichment (EE) durably improves memory performances in the Tg2576 mouse model of Alzheimer's disease (AD).

Early onset of hypersynchronous network activity and expression of a marker of chronic seizures in the Tg2576 mouse model of Alzheimer's disease.

Cortical and hippocampal hypersynchrony of neuronal networks seems to be an early event in Alzheimer's disease pathogenesis. Many mouse models of the disease also present neuronal network hypersynchrony, as evidenced by higher susceptibility to pharmacologically-induced seizures, electroencephalographic seizures accompanied by spontaneous interictal spikes and expression of markers of chronic seizures such as neuropeptide Y ectopic expression in mossy fibers. This network hypersynchrony is thought to contribute to memory deficits, but whether it precedes the onset of memory deficits or not in mouse models remains unknown.

Environmental enrichment rescues memory in mice deficient for the polysialytransferase ST8SiaIV.

The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are believed to contribute to brain structural plasticity that underlies memory formation. Indeed, the attachment of long chains of PSA to the glycoprotein NCAM down-regulates its adhesive properties by altering cell-cell interactions. In the brain, the biosynthesis of PSA is catalyzed by two polysialyltransferases, which are differentially regulated during lifespan.

Modifications of hippocampal circuits and early disruption of adult neurogenesis in the tg2576 mouse model of Alzheimer's disease.

At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction.

Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model.

Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown.

Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model.

In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities.

Transient enriched housing before amyloidosis onset sustains cognitive improvement in Tg2576 mice.

Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice--before amyloidogenesis has started--reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present.

Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model.

Alzheimer's disease (AD) results in cognitive decline and altered network activity, but the mechanisms are unknown. We studied human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Electroencephalographic recordings in hAPP mice revealed spontaneous epileptiform discharges, indicating network hypersynchrony, primarily during reduced gamma oscillatory activity.

Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network.

The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzheimer's disease (AD), which is associated with amyloid-β (Aβ) accumulation in many brain areas. Selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC caused cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. APP/Aβ overexpression in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1 and epileptiform activity in parietal cortex.

Effects of the genetic background on cognitive performances of TG2576 mice.

Animal models of genetic diseases obtained by transferring human mutated genes in the mouse are widely used in biomedical based research. They constitute efficient tools to study mechanisms underlying abnormal phenotypes. Unfortunately, the phenotype of the transgene is often obscured by the genetic background of the embryonic stem cells and that of the recipient strain used to create the transgenic line.

Paradoxical (REM) sleep genesis: the switch from an aminergic-cholinergic to a GABAergic-glutamatergic hypothesis.

In the middle of the last century, Michel Jouvet discovered paradoxical sleep (PS), a sleep phase paradoxically characterized by cortical activation and rapid eye movements and a muscle atonia. Soon after, he showed that it was still present in "pontine cats" in which all structures rostral to the brainstem have been removed. Later on, it was demonstrated that the pontine peri-locus coeruleus alpha (peri-LCalpha in cats, corresponding to the sublaterodorsal nucleus, SLD, in rats) is responsible for PS onset.

Hippocampal neurogenesis during normal and pathological aging.

It is now widely accepted that new neurons continue to be added to the brain throughout life including during normal aging. The finding of adult neurogenesis in the hippocampus, a structure involved in the processing of memories, has favored the idea that newborn neurons might subserve cognitive functions. Recent work on human post-mortem tissues and mice models of Alzheimer's disease (AD) has reported persistent hippocampal proliferative capacity during pathological aging.

Alzheimer's-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis.

Alzheimer's disease (AD) is characterized by severe neuronal loss in several brain regions important for learning and memory. Of the structures affected by AD, the hippocampus is unique in continuing to produce new neurons throughout life. Mounting evidence indicates that hippocampal neurogenesis contributes to the processing and storage of new information and that deficits in the production of new neurons may impair learning and memory.