Animal models of tinnitus allow us to study the relationship between changes in neural activity and the tinnitus percept. Here, guinea pigs were subjected to unilateral noise trauma and tested behaviourally for tinnitus 8 weeks later. By comparing animals with tinnitus with those without, all of which were noise-exposed, we were able to identify changes unique to the tinnitus group. Three physiological markers known to change following noise exposure were examined: spontaneous firing rates (SFRs) and burst firing in the inferior colliculus (IC), evoked auditory brainstem responses (ABRs), and the number of neurons in the cochlear nucleus containing nitric oxide synthase (NOS). We obtained behavioural evidence of tinnitus in 12 of 16 (75%) animals. Both SFRs and incidences of burst firing were elevated in the IC of all noise-exposed animals, but there were no differences between tinnitus and no-tinnitus animals. There were significant decreases in ipsilateral ABR latencies in tinnitus animals, contrary to what might be expected with a small hearing loss. Furthermore, there was an ipsilateral–contralateral asymmetry in NOS staining in the ventral cochlear nucleus (VCN) that was only apparent in tinnitus animals. Tinnitus animals had a significantly greater number of NOS-containing neurons on the noise-exposed side, whereas no-tinnitus animals did not. These data suggest that measuring NOS in the VCN and recording ABRs supplement behavioural methods for confirming tinnitus in animals, and that nitric oxide is involved in plastic neural changes associated with tinnitus.
Highlights► Prepulse inhibition can be reliably and robustly measured using the Preyer reflex. ► The Preyer reflex is a more reliable response than the whole-body startle in guinea pigs. ► Salicylate impairs gap detection at specific background noise frequencies, indicating the presence of tinnitus. ► Measuring gap detection using the Preyer reflex is a suitable method for identifying tinnitus.
Gender differences in both vulnerability to stroke and outcome following cerebral ischaemia have frequently been observed and attributed to the action of steroid hormones. Progesterone is a candidate neuroprotective factor for stroke; however, studies are lacking which: (i) study those groups representing high risk i.e. postmenopausal females; (ii) administer progesterone solely post-ischaemia; and (iii) combine histopathological and functional assessments. Postmenopausal females, along with males, represent the group at highest risk of cerebral stroke and can be modelled using aged or ovariectomized animals. In the current study, we aimed to determine the neuroprotective effects of progesterone administration following cerebral ischaemia in aged and ovariectomized mice. Following transient middle cerebral artery occlusion, progesterone was administered at 1, 6 and 24 h post-ischaemia to aged and ovariectomized female mice. At 48 h post-ischaemia, progesterone significantly reduced the lesion volume (P< 0.05) but had no effect on neurological outcome in aged female mice. Whereas in ovariectomized mice, at 48 h post-ischaemia, progesterone treatment had no effect on the amount of lesion volume present but did significantly improve neurological outcome. In a further study of ovariectomized mice, allowed to survive for 7 days post-ischaemia, progesterone treatment significantly improved motor outcome as assessed using both the rotarod and grid test. In fact, by 7 days post-ischaemia, progesterone-treated ovariectomized mice did not differ significantly in performance compared with shams, whereas vehicle-treated ovariectomized mice displayed a significant functional impairment following ischaemia. The current study has demonstrated that progesterone has different neuroprotective effects whether it is administered to aged or ovariectomized female mice and emphasizes the need to combine histopathological and functional outcomes within the same study. In addition, as progesterone-only treatment may not improve all outcomes in all groups, therapies that combine progesterone with other neuroprotective candidates should be investigated to maximize benefit following stroke.
Tinnitus chronically affects between 10-15% of the population but, despite its prevalence, the underlying mechanisms are still not properly understood. One experimental model involves administration of high doses of sodium salicylate, as this is known to reliably induce tinnitus in both humans and animals. Guinea pigs were implanted with chronic electrocorticography (ECoG) electrode arrays, with silver-ball electrodes placed on the dura over left and right auditory cortex. Two more electrodes were positioned over the cerebellum to monitor auditory brainstem responses (ABRs). We recorded resting-state and auditory evoked neural activity from awake animals before and 2 h following salicylate administration (350 mg/kg; i.p.). Large increases in click-evoked responses (> 100%) were evident across the whole auditory cortex, despite significant reductions in wave I ABR amplitudes (in response to 20 kHz tones), which are indicative of auditory nerve activity. In the same animals, significant decreases in 6-10 Hz spontaneous oscillations (alpha waves) were evident over dorsocaudal auditory cortex. We were also able to demonstrate for the first time that cortical evoked potentials can be inhibited by a preceding gap in background noise [gap-induced pre-pulse inhibition (PPI)], in a similar fashion to the gap-induced inhibition of the acoustic startle reflex that is used as a behavioural test for tinnitus. Furthermore, 2 h following salicylate administration, we observed significant deficits in PPI of cortical responses that were closely aligned with significant deficits in behavioural responses to the same stimuli. Together, these data are suggestive of neural correlates of tinnitus and oversensitivity to sound (hyperacusis).
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