Anxiety disorders, such as post-traumatic stress, are more prevalent in women and are characterized by impaired inhibition of learned fear and medial prefrontal cortex (mPFC) dysfunction. Here we examined sex differences in fear extinction and mPFC activity in rats. Females showed more learned fear expression during extinction and its recall, but not fear conditioning. They also showed more spontaneous fear recovery and more contextual fear before extinction and its recall. Moreover, enhanced learned fear expression in females was associated with sustained prelimbic (PL) cortex activity. These results suggest that sex differences in learned fear expression may involve persistent PL activation.Women are at increased risk of developing fear-related anxiety disorders compared to men. For example, the prevalence of posttraumatic stress disorder (PTSD) is twice as high in women as in men (Lebron-Milad and Milad 2012). These disorders are characterized by impaired inhibition of learned fear (Milad et al. 2009a;Jovanovic et al. 2010) and a growing number of studies in humans and animals have shown sex differences in fear extinction (Milad et al. 2006;Baran et al. 2009Baran et al. , 2010Glover et al. 2012;ter Horst et al. 2012;Baker-Andresen et al. 2013), the reduction in learned fear that occurs with repeated nonreinforced presentations of the conditioned stimulus (CS).The neural circuitry mediating fear extinction is dysfunctional in PTSD. The medial prefrontal cortex (mPFC) is a heterogeneous area that plays a crucial role in this circuit through its involvement in learned fear and extinction processing. The dorsal anterior cingulate cortex (dACC) in humans and its rodent homolog, the prelimbic cortex (PL), are important for conditioned fear expression. In contrast, the human ventromedial prefrontal cortex (vmPFC) and the homologous infralimbic cortex (IL) in rodents are involved in fear suppression and extinction (Vidal-Gonzalez et al. 2006;Sierra-Mercado et al. 2011;Linnman et al. 2012). Importantly, PTSD is associated with dACC and vmPFC dysfunction (Milad et al. 2009a;Shin et al. 2009). Although a role for mPFC in mediating sex differences in fear extinction is emerging (Baran et al. 2010;Zeidan et al. 2011;Merz et al. 2012), the potential contribution of individual mPFC subregions remains unknown.We examined sex differences in local field potential (LFP) activity in PL and IL during fear extinction in male and naturally cycling female Lister hooded rats (Harlan, UK). All experimental procedures were conducted with internal ethical approval and in accordance with the Animals (Scientific Procedures) Act 1986, UK. Electrodes (Teflon-coated stainless-steel wires, 50 mm diameter) were implanted into PL and IL (2.7 mm anterior and 0.5 mm lateral to bregma, 3.3 mm (PL) and 4.3 mm (IL) ventral to the brain surface) under isoflurane anesthesia. Rats received peri-and post-operative analgesia (buprenorphine and meloxicam) and were singly housed during recovery and behavioral testing, which started 10 -14 d after surgery. ...

Sex differences in learned fear expression and extinction involve the medial prefrontal cortex (mPFC). We recently demonstrated that enhanced learned fear expression during auditory fear extinction and its recall is linked to persistent theta activation in the prelimbic (PL) but not infralimbic (IL) cortex of female rats. Emerging evidence indicates that gamma oscillations in mPFC are also implicated in the expression and extinction of learned fear. Therefore we re-examined our in vivo electrophysiology data and found that females showed persistent PL gamma activation during extinction and a failure of IL gamma activation during extinction recall. Altered prefrontal gamma oscillations thus accompany sex differences in learned fear expression and its extinction. These findings are relevant for understanding the neural basis of post-traumatic stress disorder, which is more prevalent in women and involves impaired extinction and mPFC dysfunction.

Acoustic overexposure, such as listening to loud music too often, results in noise-induced hearing loss. The pathologies of this prevalent sensory disorder begin within the ear at synapses of the primary auditory receptors, their postsynaptic partners and their supporting cells. The extent of noise-induced damage, however, is determined by over-stimulation of primary auditory receptors, upstream of where the pathologies manifest. A systematic characterisation of the electrophysiological function of the upstream primary auditory receptors is warranted to understand how noise-exposure impacts on downstream targets, where the pathologies of hearing loss begin. Here, we used the experimentally-accessible locust ear (male, Schistocerca gregaria) to characterise a decrease in the auditory receptor's ability to respond to sound after noise exposure. Surprisingly, after noise exposure, the electrophysiological properties auditory receptors remains unchanged, despite a decrease in the ability to transduce sound. This auditory deficit stems from changes in a specialised receptor lymph that bathes the auditory receptors-revealing striking parallels with the mammalian auditory system. Significance Statement Noise exposure is the largest preventable cause of hearing loss. It is the auditory receptors that bear the initial brunt of excessive acoustic stimulation, because they must convert excessive soundinduced movements into electrical signals, but remain functional afterward. Here we use the accessible ear of an invertebrate to-for the first time in any animal-characterise changes in auditory receptors after noise overexposure. We find that their decreased ability to transduce sound into electrical signals is, most probably, due to changes in supporting (scolopale) cells that maintain the ionic composition of the ear. An emerging doctrine in hearing research is that vertebrate primary auditory receptors are surprisingly robust, something which we show rings true for invertebrate ears too.

Associative learning is encoded under anesthesia and involves the medial prefrontal cortex (mPFC). Neuronal activity in mPFC increases in response to a conditioned stimulus (CS+) previously paired with an unconditioned stimulus (US) but not during presentation of an unpaired stimulus (CS-) in anesthetized animals. Studies in conscious animals have shown dissociable roles for different mPFC subregions in mediating various memory processes, with the prelimbic (PL) and infralimbic (IL) cortex involved in the retrieval and extinction of conditioned responding, respectively. Therefore PL and IL may also play different roles in mediating the retrieval and extinction of discrimination learning under anesthesia. Here we used in vivo electrophysiology to examine unit and local field potential (LFP) activity in PL and IL before and after auditory discrimination learning and during later retrieval and extinction testing in anesthetized rats. Animals received repeated presentations of two distinct sounds, one of which was paired with footshock (US). In separate control experiments animals received footshocks without sounds. After discrimination learning the paired (CS+) and unpaired (CS-) sounds were repeatedly presented alone. We found increased unit firing and LFP power in PL and, to a lesser extent, IL after discrimination learning but not after footshocks alone. After discrimination learning, unit firing and LFP power increased in PL and IL in response to presentation of the first CS+, compared to the first CS-. However, PL and IL activity increased during the last CS- presentation, such that activity during presentation of the last CS+ and CS- did not differ. These results confirm previous findings and extend them by showing that increased PL and IL activity result from encoding of the CS+/US association rather than US presentation. They also suggest that extinction may occur under anesthesia and might be represented at the neural level in PL and IL.

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