Research has identified distinct neuronal circuits within the basolateral amygdala (BLA) that differentially mediate fear expression versus inhibition; however, molecular markers of these populations remain unknown. Here we examine whether optogenetic activation of a cellular subpopulation, which may correlate with the physiologically identified extinction neurons in the BLA, would differentially support fear conditioning versus fear inhibition/extinction. We first molecularly characterized Thy1-channelrhodopsin-2 (Thy1-ChR2-EYFP)-expressing neurons as a subpopulation of glutamatergic pyramidal neurons within the BLA. Optogenetic stimulation of these neurons inhibited a subpopulation of medial central amygdala neurons and shunted excitation from the lateral amygdala. Brief activation of these neurons during fear training disrupted later fear memory in male mice. Optogenetic activation during unreinforced stimulus exposure enhanced extinction retention, but had no effect on fear expression, locomotion, or open-field behavior. Together, these data suggest that the Thy1-expressing subpopulation of BLA pyramidal neurons provide an important molecular and pharmacological target for inhibiting fear and enhancing extinction and for furthering our understanding of the molecular mechanisms of fear processing.

Thy1-Expressing Neurons in the Basolateral Amygdala May Mediate Fear Inhibition

Alzheimer's disease (AD) is a chronic neurodegenerative disorder which can contribute to memory loss and cognitive damage in the elderly; moreover, evidence from clinical and animal studies demonstrated that AD always exhibit severe cognitive deficits. However, the effects of donepezil medications on cognition are controversial. Additionally, it is unclear whether donepezil can protect neurons to improve cognitive function through the brain-derived neurotropic factor (BDNF)/tyrosine receptor kinase B (TrkB) signalling pathway in the tree shrew (TS), which has a closer evolutionary relationship to primates than rodents. Here, we designed a study on an amyloid-β1-40 (Aβ1-40)-induced TS model of AD and investigated the molecular mechanism by which donepezil protects neurons and improves cognitive function through activating the BDNF/TrkB signalling pathway. The results showed that donepezil could rescue Aβ1-40-induced spatial cognition deficits, and reverse Aβ1-40-induced temporal horn along with ADC enlargement in the TS brain. Meanwhile, it suppressed Aβ1-40-induced neuronal damage and loss of body weight. Intriguingly, donepezil could increase the choline acetyl transferase (ChAT) expression level and reduce the fibrillary acid protein (GFAP) expression level in the hippocampus and cortex of TS. Additionally, donepezil significantly upregulated the expression level of BDNF, as well as the phosphorylated level of TrkB. These results suggested that donepezil could protect neurocytes from senility and ameliorate learning and memory impairment in the TS model of AD, which appeared to be through regulating the cholinergic system and inhibiting the BDNF/TrkB-dependent signalling pathway. Moreover, the study underlines the potency of TS to be a novel animal model for research on AD, and it deserves intensive attention.

Donepezil improves the cognitive impairment in a tree shrew model of Alzheimer’s disease induced by amyloid-β1–40 via activating the BDNF/TrkB signal pathway

Understanding human sleep requires appropriate animal models. Sleep has been extensively studied in rodents, although rodent sleep differs substantially from human sleep. Here we investigate sleep in tree shrews, small diurnal mammals phylogenetically close to primates, and compare it to sleep in rats and humans using electrophysiological recordings from frontal cortex of each species. Tree shrews exhibited consolidated sleep, with a sleep bout duration parameter, τ, uncharacteristically high for a small mammal, and differing substantially from the sleep of rodents that is often punctuated by wakefulness. Two NREM sleep stages were observed in tree shrews: NREM, characterized by high delta waves and spindles, and an intermediate stage (IS-NREM) occurring on NREM to REM transitions and consisting of intermediate delta waves with concomitant theta-alpha activity. While IS-NREM activity was reliable in tree shrews, we could also detect it in human EEG data, on a subset of transitions. Finally, coupling events between sleep spindles and slow waves clustered near the beginning of the sleep period in tree shrews, paralleling humans, whereas they were more evenly distributed in rats. Our results suggest considerable homology of sleep structure between humans and tree shrews despite the large difference in body mass between these species. Dimanico et al investigated sleep in tree shrews using electrophysiological recordings and compared it to equivalent read-outs in rats and humans. They reported that there was considerable homology of sleep structure between humans and tree shrews despite the difference in body mass between these species.

/pdf/aspects-of-tree-shrew-consolidated-sleep-structure-resemble-3jfyidtjzl.pdf

Aspects of tree shrew consolidated sleep structure resemble human sleep.

Mapping of c-Fos expression in male tree shrew forebrain.

In humans, cues associated with the rewarding effect of drugs of abuse induce drug craving and activate drug-associated memories after prolonged abstinence. In animal studies with the self-administration (SA) paradigm, responses to drug-associated cues increase within time after extinction, a phenomenon described as incubation of craving. Conditioned place preference (CPP) is widely used to measure the rewarding effect of drugs and the reward memory thereof. However, little is known whether responses to drug associated cues progressively increase after abstinence from the drugs in the CPP paradigm. To test whether the drug-associated cues could increase specific responses over the abstinence period in the CPP paradigm, we employed the high dose morphine-induced CPP paradigms in rats and tree shrews in the present study. We examined the CPP scores and the entrances to side chambers of the CPP apparatus to check whether they would progressively increase in the CPP paradigms. Twenty-one male adult Sprague-Dawley rats and eight adult male tree shrews were used to establish morphine-induced CPP and another ten rats treated with saline were controls for the rat experiments. After morphine conditioning, rats and tree shrews showed significant higher CPP scores at the first or second post tests than at baseline but then the CPP scores in the abstinence period decreased gradually. During the abstinence period, animals with morphine-conditioning experiences entered progressively more times to both side compartments, whereas the number of entrances to side chambers of the saline group in rats had no such significant differences. These findings suggest that progressively increased entrances to the side chambers in the extended abstinence period reflect the incubation of craving in high dose morphine-induced CPP paradigms. Also, our data imply that reward memory and drug craving can be distinguished in the CPP paradigm.

Increased entrances to side compartments indicate incubation of craving in morphine-induced rat and tree shrew CPP models

Fear is an emotion that is well-studied due to its importance for animal survival. Experimental animals, such as rats and mice, have been widely used to model fear. However, higher animals such as nonhuman primates have rarely been used to study fear due to ethical issues and high costs. Tree shrews are small mammals that are closely related to primates; they have been used to model human-related psychosocial conditions such as stress and alcohol tolerance. Here, we describe an experimental paradigm to study the formation and extinction of fear memory in tree shrews. We designed an experimental apparatus of a light/dark box with a voltage foot shock. We found that tree shrews preferred staying in the dark box in the daytime without stimulation and showed avoidance to voltage shocks applied to the footplate in a voltage-dependent manner. Foot shocks applied to the dark box for 5 days (10 min per day) effectively reversed the light-dark preference of the tree shrews, and this memory lasted for more than 50 days without any sign of memory decay (extinction) in the absence of further stimulation. However, this fear memory was reversed with 4 days of reverse training by applying the same stimulus to the light box. When reducing the stimulus intensity during the training period, a memory extinction and subsequently reinstatement effects were observed. Thus, our results describe an efficient method of monitoring fear memory formation and extinction in tree shrews.

/pdf/the-formation-and-extinction-of-fear-memory-in-tree-shrews-oi1io8g5vr.pdf

The formation and extinction of fear memory in tree shrews.

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The formation and extinction of fear memory in tree shrews.