Aversive olfactory associative memory loses odor specificity over time.

Avoiding associatively learned predictors of danger is crucial for survival. Aversive memories can, however, become counter-adaptive when they are overly generalized to harmless cues and contexts. In a fruit fly odor-electric shock associative memory paradigm, we found that learned avoidance lost its specificity for the trained odor and became general to novel odors within a day of training. We discuss the possible neural circuit mechanisms of this effect and highlight the parallelism to over-generalization of learned fear behavior after an incubation period in rodents and humans, with due relevance for post-traumatic stress disorder.

Nasal administration of orexin A partially rescues dizocilpine-induced cognitive impairments in female C57BL/6 J mice.

Sex difference has been reported in several behavioral endophenotypes of neuropsychiatric disorder in both rodents and humans. However, sex difference in cognitive symptoms associated with neuropsychiatric disorders has not been studied in detail. In this study, we induced cognitive impairment using the NMDA receptor antagonist, dizocilpine (MK-801), in male and female C57BL/6 J mice and performed a visual discrimination task in an automated touchscreen system. We found that discrimination performance decreased with increased doses of MK-801 in both sexes. However, female mice showed stronger deficit in discrimination performance than the male mice especially after administration of low (0.01 mg/kg) and high (0.15 mg/kg) doses of MK-801. Furthermore, we tested if administration of orexin A, orexin-1 receptor antagonist SB-334867 or orexin-2 receptor antagonist EMPA rescued MK-801 (0.15 mg/kg) induced cognitive impairment in visual discrimination. We found that nasal administration of orexin A partially rescued the cognitive impairment induced by MK-801 in females but not in males. Taken together, our data show that female C57BL/6 J mice are more sensitive compared to males to some doses of MK-801 in discrimination learning task and that orexin A partially rescues this cognitive impairment in females.

Intracerebroventricular infusion of the selective orexin 1 receptor antagonist SB-334867 impairs cognitive flexibility in a sex-dependent manner.

Orexin neuropeptides are well known for their role in sleep/wake cycle, feeding behavior and motivation-related behaviors. However, their role in cognition is not clearly understood. We recently published that orexin deficiency impairs intra-dimensional set shifting in female homozygous orexin-deficient mice but improves the first reversal phase in male homozygous orexin-deficient mice in the attentional set shifting task (ASST), a well-established rodent test for cognitive flexibility. In the present study, we tested if intracerebroventricular injections of the selective orexin 1 receptor antagonist SB-334867 (4 µg/2 µL) affects cognitive flexibility in the different phases of ASST. We found that SB-334867 injections impaired the first and second reversal phases in female C57BL/6J mice but not in males. In addition, we also showed that at this particular dose of SB-334867, the consumption of the reward that was used in the ASST was not affected in both males and females. Our findings indicate that cognitive flexibility is impaired by orexin 1 receptor antagonism in a sex-dependent manner and reiterates the sexually dimorphic role of orexin in cognitive flexibility.

Orexin deficiency modulates cognitive flexibility in a sex-dependent manner.

Cognitive flexibility is an important executive function and refers to the ability to adapt behaviors in response to changes in the environment. Of note, many brain disorders are associated with impairments in cognitive flexibility. Several classical neurotransmitter systems including dopamine, acetylcholine and noradrenaline are shown to be important for cognitive flexibility, however, there is not much known about the role of neuropeptides. The neuropeptide orexin, which is brain-widely released by neurons in the lateral hypothalamus, is a major player in maintaining sleep/wake cycle, feeding behavior, arousal, and motivational behavior. Recent studies showed a role of orexin in attention, cognition and stress-induced attenuation of cognitive flexibility by disrupting orexin signaling locally or systemically. However, it is not known so far whether brain-wide reduction or loss of orexin affects cognitive flexibility. We investigated this question by testing male and female orexin-deficient mice in the attentional set shifting task (ASST), an established paradigm of cognitive flexibility. We found that orexin deficiency impaired the intra-dimensional shift phase of the ASST selectively in female homozygous orexin-deficient mice and improved the first reversal learning phase selectively in male homozygous orexin-deficient mice. We also found that these orexin-mediated sex-based modulations of cognitive flexibility were not correlated with trait anxiety, narcoleptic episodes, and reward consumption. Our findings highlight a sexually dimorphic role of orexin in regulating cognitive flexibility and the need for further investigations of sex-specific functions of the orexin circuitry.

BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment.

Brain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF's role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF+/-) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/- mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/- mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/- mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.

Functional architecture of reward learning in mushroom body extrinsic neurons of larval Drosophila.

The brain adaptively integrates present sensory input, past experience, and options for future action. The insect mushroom body exemplifies how a central brain structure brings about such integration. Here we use a combination of systematic single-cell labeling, connectomics, transgenic silencing, and activation experiments to study the mushroom body at single-cell resolution, focusing on the behavioral architecture of its input and output neurons (MBINs and MBONs), and of the mushroom body intrinsic APL neuron. Our results reveal the identity and morphology of almost all of these 44 neurons in stage 3 Drosophila larvae. Upon an initial screen, functional analyses focusing on the mushroom body medial lobe uncover sparse and specific functions of its dopaminergic MBINs, its MBONs, and of the GABAergic APL neuron across three behavioral tasks, namely odor preference, taste preference, and associative learning between odor and taste. Our results thus provide a cellular-resolution study case of how brains organize behavior.