Abstract
Visual cortical areas show enhanced tactile responses in blind individuals, resulting in improved behavioral performance. Induction of unilateral vision loss in adult mice, by monocular enucleation (ME), is a validated model for such cross-modal brain plasticity. A delayed whisker-driven take-over of the medial monocular zone of the visual cortex is preceded by so-called unimodal plasticity, involving the potentiation of the spared-eye inputs in the binocular cortical territory. Full reactivation of the sensory-deprived contralateral visual cortex is accomplished by 7 weeks post-injury. Serotonin (5-HT) is known to modulate sensory information processing and integration, but its impact on cortical reorganization after sensory loss, remains largely unexplored. To address this issue, we assessed the involvement of 5-HT in ME-induced cross-modal plasticity and the 5-HT receptor (5-HTR) subtype used. We first focused on establishing the impact of ME on the total 5-HT concentration measured in the visual cortex and in the somatosensory barrel field. Next, the changes in expression as a function of post-ME recovery time of the monoamine transporter 2 (vMAT2), which loads 5-HT into presynaptic vesicles, and of the 5-HTR1A and 5-HTR3A were assessed, in order to link these temporal expression profiles to the different types of cortical plasticity induced by ME. In order to accurately pinpoint which 5-HTR exactly mediates ME-induced cross-modal plasticity, we pharmacologically antagonized the 5-HTR1A, 5-HTR2A and 5-HTR3A subtypes. This study reveals brain region-specific alterations in total 5-HT concentration, time-dependent modulations in vMAT2, 5-HTR1A and 5-HTR3A protein expression and 5-HTR antagonist-specific effects on the post-ME plasticity phenomena. Together, our results confirm a role for 5-HTR1A in the early phase of binocular visual cortex plasticity and suggest an involvement of 5-HTR2A and 5-HTR3A but not 5-HTR1A during the late cross-modal recruitment of the medial monocular visual cortex. These insights contribute to the general understanding of 5-HT function in cortical plasticity and may encourage the search for improved rehabilitation strategies to compensate for sensory loss.
Highlights
Even though the mammalian brain is most susceptible to changes in sensory inputs during so-called critical periods early in life [1,2,3,4], it retains the intrinsic capacity to recover from sensory deprivation well into adulthood [1, 5,6,7]
Mice with a 3 week post-monocular enucleation (ME) recovery period (3wME) are at the end of the open-eye potentiation phase, which restores normal visually driven activity levels in an extended binocular zone (Bz). 5 weeks post-ME (5wME) mice are in an ongoing cross-modal phase whereas mice with a 7 week post-ME recovery period (7wME) have undergone maximal cross-modal visual cortex reactivation in which normal activity levels are restored in the monocular zone of the visual cortex, especially medial to the Bz (Mmz), only relying on whisker inputs
Reduced visual cortex 5-HT concentration in response to monocular enucleation To investigate if 5-HT is involved in adult ME-induced cross-modal plasticity and to better understand its role therein, we first examined whether the total 5-HT concentration was affected in the two cortices that functionally adapt upon ME
Summary
Even though the mammalian brain is most susceptible to changes in sensory inputs during so-called critical periods early in life [1,2,3,4], it retains the intrinsic capacity to recover from sensory deprivation well into adulthood [1, 5,6,7]. Of particular interest to the field of cortical plasticity are the serotonergic G-protein coupled receptors 5-HTR1A and 5-HTR2A, and ion channel 5-HTR3A These receptors are most abundantly expressed in the mammalian neocortex, predominantly on excitatory, excitatory and inhibitory, and exclusively on inhibitory neurons respectively. Administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine during a period of visual deprivation via eyelid suture reinstated juvenile-like unimodal ocular dominance plasticity in adulthood. This extraordinary phenomenon was found to be mediated through, amongst others, changes in 5-HTR1A receptor function leading to an experiencedependent shift in the cortical excitation/inhibition balance (E/I) [26, 27, 36, 42, 43]. 2 days of visual deprivation in young rats mediated a 5-HTR2A/ 2C-dependent delivery of AMPAR1 at layer IV-II/III synapses of the primary somatosensory barrel cortex (S1BF), leading to compensatory plasticity in the form of a sharpened whisker-barrel map and more fine-tuned barrel neuron responses to primary whisker stimulation [32]
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