Conference Agenda

In addition to metabolic and cardiovascular disorders, obesity is associated with memory dysfunction in humans and animals models. Interestingly, we have recently shown that alterations of the hippocampal endocannabinoid system and its main receptor CB1R, well known to regulate brain plasticity and memory processes, participates in memory deficits in male mice fed with an obesogenic high-fat diet (HFD). Indeed, systemic CB1R blockade or decrease of hippocampal CB1R improved memory in HFD-fed males. This project aims at identifying whether the endocannabinoid-CB1R system contributes to HFD-induced memory deficits in females and whether similar mechanisms (brain structures and cell types) are involved.

First, we showed that systemic injection of a CB1R antagonist rescued deficits of long-term object recognition memory in HFD-fed females, as in males, indicating CB1R signaling regulates the impact of HFD on memory function in both sexes. However, contrary to males, decrease of hippocampal CB1R in HFD-fed females did not improve recognition memory deficits. Interestingly, decrease of CB1R in the medial prefrontal cortex (similar in both sexes) rescued recognition memory deficits in females, but not males. These results show a double dissociation in hippocampal and prefrontal CB1R regulation of HFD effect on memory in females and males.

Furthermore, whereas hippocampal CB1R on glutamatergic (but not GABAergic) neurons are involved in memory deficits in HFD-fed males, prefrontal CB1R on GABAergic (but not glutamatergic) neurons are involved in HFD-fed females.

We finally wondered whether these sexual differences could be mediated by ovarian hormones. Ovariectomy by itself did not affect HFD-induced memory deficits in females, but decrease of hippocampal, but not prefrontal, CB1R improves memory deficits in ovariectomized HFD-fed females.

Altogether our results indicate that endocannabinoid-CB1R system is involved in HFD-induced memory deficits in both sexes but brain structures and cells types involved differ between males and females through a modulation from ovarian hormones.

New memories undergo a prolonged process of stabilization or “consolidation” in order to be maintained for a long time. Memory consolidation occurs at cellular level, with changes in synaptic transmission and strength, and at system level, with a time-dependent reorganization of brain circuits that, over time, favors cortical regions in the memories storage and retrieval. Memories embedded with emotional content, in particular, by influencing behaviors and decisions, are the core of humans and animals life. However, whether and how previous emotive experiences shape the consolidation of novel memories is poorly understood. Here we demonstrated how prior fear learning allows the cortical regions to directly encode new and similar aversive memories only through the cellular mechanisms of synaptic consolidation. The behavioral expression of the emotional response related to the retrieval of both past and recent fearful memories requires the functional connection between these cortical areas and the basolateral amygdala. Here we discuss how the reorganization of circuits that characterizes system consolidation occurs only in the first instance that an event is learned, subsequently allowing the immediate assimilation of new analogous events in final storage sites.

The ability to memorize stimuli enables one to react differently to novel and familiar stimuli. This ability is fundamental for normal life and impaired in many brain pathologies, including stress-induced maladaptive behaviours. Several brain structures and signals are critical for the formation of different types of memory. The hypothalamus contains histaminergic neurons that innervate brain areas critical for memory control. Genetic, pharmacological and electrophysiological manipulations have greatly contributed to the understanding of how the histaminergic system in the brain affect learning and memory and fine-tune different behavioural responses. Recently, designer receptors activated by designer drugs (DREADDs) technology has been used to control the activity of histaminergic neurons which are located in the hypothalamic tuberomamillary nucleus (TMN^HA) permitting a temporal, cellular and regional specificity, which is hardly afforded by pharmacological or genetic manipulations. Here, we used non-rewarded, spontaneous learning tasks using objects or conspecific, to question the effect of chemogenetic activation or inhibition of TMN^HA neurons. HDC-Cre mice were injected into the TMN with excitatory or inhibitory DREADDs. The DREADDs activator clozapine-N-oxide was injected at different timing during the behavioural tests in physiological conditions as well as after repeated social stress. We observed opposite effects of activation or inhibition of TMN^HA neurons. Chemogenetic activation of TMN^HA neurons lead to an improvement of social and object memories, whereas with inhibition an impairment was apparent. In particular, targeting the HA system modulated both the acquisition and the retrieval of the tested memories in normal mice and, notably, in stressed mice. We revealed that chemogenetic activation or inhibition of TMN^HA cells results in facilitation or impairment of memory, respectively, and such effects overcame the memory impairments induced by stress. These results pave the way for future studies to deconstruct specific histaminergic pathways and regulatory mechanisms underlying the control of memory in health and diseases.

The process of memory consolidation involves the transfer of information from short-term memory (STM) to long-term memory (LTM). Memory consolidation requires activation of the dorsal hippocampus (dHP), especially under conditions of high memory load. In this study, we asked whether there is a limit to the memory capacity, that is, the amount of information that can be stored during unique experiences. Using male and female outbred CD1 mice subjected to a modified version of the object recognition test, we found that females, despite having the same 6-object STM capacity as males, appear to transfer only 4 objects into the LTM, whereas males remember all 6. Using c-Fos expression as a marker of neural activation, we found that female mice show greater activation of the ventral median thalamus (VMT), while males hyperactivate the dHP, when exposed to 6 objects to remember. Optogenetic inhibition of the VMT-dHP pathway during off-line memory consolidation allowed the maintenance of the 6-object LTM in females, whereas chemogenetic activation of VMT-dHP impairs it in males. These results identify a subcortical-cortical circuit sensitive to biological sex differences that controls the amount of information spontaneously transferred from the STM to the LTM.