Evaluation of Crowdsourced Fundraising to Cover Health Care Costs for Neurological Conditions in the US.

This cross-sectional study characterizes the use of and rationale for crowdsourced fundraising by patients with neurological illnesses and their family members.

Diminished Fear Extinction in Adolescents Is Associated With an Altered Somatostatin Interneuron-Mediated Inhibition in the Infralimbic Cortex.

BACKGROUND: Rodents and humans show an attenuation of fear extinction during adolescence, which coincides with the onset of several psychiatric disorders. Although the ethological relevance and the underlying mechanism are largely unknown, the suppression of fear extinction during adolescence is associated with a diminished plasticity in the glutamatergic neurons of the infralimbic medial prefrontal cortex, a brain region critical for fear extinction. Given the putative effect of synaptic inhibition on glutamatergic neuron activity, we studied whether gamma-aminobutyric acidergic neurons in the infralimbic medial prefrontal cortex are involved in the suppression of fear extinction during adolescence. METHODS: We assessed membrane and synaptic properties in parvalbumin-positive interneurons (PVINs) and somatostatin-positive interneurons (SSTINs) in male preadolescent, adolescent, and adult mice. The effect of fear conditioning and extinction on PVIN-pyramidal neuron and SSTIN-pyramidal neuron synapses in male preadolescent, adolescent, and adult mice was evaluated using an optogenetic approach. RESULTS: The development of the membrane excitability of PVINs is delayed and reaches maturity only by adulthood, while the SSTIN membrane properties are developed early and remain stable during development from preadolescence to adulthood. Although the synaptic inhibition mediated by PVINs undergoes a protracted development, it does not exhibit a fear behavior-specific plasticity. However, the synaptic inhibition mediated by SSTINs undergoes an adolescence-specific enhancement, and this increased inhibition is suppressed by fear learning but is not restored by extinction training. This altered plasticity during adolescence overlapped with a reduction in calcium-permeable glutamate receptors in SSTINs. CONCLUSIONS: The adolescence-specific plasticity in the SSTINs might play a role in fear extinction suppression during adolescence in mice.

Lack of experience-dependent intrinsic plasticity in the adolescent infralimbic medial prefrontal cortex.

Fear extinction, an inhibitory learning that suppresses a previously learned fear memory, is diminished during adolescence. Earlier studies have shown that this suppressed fear extinction during adolescence involves an altered glutamatergic plasticity in infralimbic medial prefrontal cortical (IL-mPFC) pyramidal neurons. However, it is unclear whether the excitability of IL-mPFC pyramidal neurons plays a role in this development-dependent suppression of fear extinction. Therefore, we examined whether fear conditioning and extinction affect the active and passive membrane properties of IL-mPFC layer 5 pyramidal neurons in preadolescent, adolescent and adult mice. Both preadolescent and adult mice exhibited a bidirectional modulation of the excitability of IL-mPFC layer 5 pyramidal neurons following fear conditioning and extinction, i.e., fear conditioning reduced membrane excitability, whereas fear extinction reversed this effect. However, the fear conditioning-induced suppression of excitability was not reversed in adolescent mice following fear extinction training. Neither fear conditioning nor extinction affected GABAergic transmission in IL-mPFC layer 5 pyramidal neurons, suggesting that GABAergic transmission did not play a role in experience-dependent modulation of neuronal excitability. Our results suggest that the extinction-specific modulation of excitability is impaired during adolescence.

Development- and experience-dependent plasticity in the dorsomedial habenula.

Of the two major subdivisions of the habenula, the medial and lateral nuclei, the medial habenula is the least understood in terms of synaptic transmission, intrinsic properties and plasticity. The medial habenula (MHb) is composed of glutamatergic neurons which receive the majority of their inputs from the septal region and project predominantly to the interpeduncular nucleus (IPN). To understand the synaptic transmission, we studied both glutamatergic and GABAergic synaptic transmission in the dorsal region of the medial habenula (dMHb). While glutamatergic transmission dominates during early development, an attenuation of glutamatergic transmission and an enhancement of GABAergic transmission occur during development leading into adulthood. Furthermore, as reported previously, GABAA receptor-mediated transmission is excitatory in the adult dMHb, which is consistent with the reduced expression of the K-Cl co-transporter KCC2. Given the potential role of the dMHb in aversive behaviors, we examined whether fear conditioning or exposure to foot shock affects excitability in dMHb neurons. We observed a suppression of the excitability of dMHb neurons in mice that either underwent fear conditioning or were exposed to foot shock. Furthermore, we observed a suppression of GABAergic but not glutamatergic transmission in the dMHb neurons following fear conditioning. These results suggest that aversive experience produces a suppression of the dMHb neuronal activity. Given that the medial habenula is upstream of the median raphe nucleus which is believed to be involved in the negative regulation of aversive memory, the suppression of dMHb neurons following an aversive experience might play a role in strengthening of aversive memories.

Alteration of the Centromedial Amygdala Glutamatergic Synapses by the BDNF Val66Met Polymorphism.

Fear expression is mediated by an activation of the centromedial amygdala (CEm), the major output nucleus of the amygdaloid complex. Consistently, fear extinction is associated with an increased synaptic inhibition as well as a suppression of the excitability of the CEm neurons. However, little is known about the role of CEm glutamatergic synapses in fear regulation and anxiety-like behaviors. The BDNF Val66Met, a single-nucleotide polymorphism in the human BDNF gene, impairs fear extinction and leads to anxiety-like symptoms. To determine whether the BDNF Val66Met polymorphism affects the CEm excitatory synapses, we examined basal glutamatergic synaptic transmission and plasticity in the CEm neurons of BDNF Val66Met knock-in (BDNF(Met/Met)) mice. The BDNF Val66Met single-nucleotide polymorphism exerted an opposite effect on non-NMDA and NMDA receptor transmission with a potentiation of the former and a suppression of the latter. In addition, the decay time of NMDA currents was decreased in BDNF(Met/Met) mice, suggesting a modification of NMDA receptor subunit composition. Unlike the wild-type mice that exhibited a potentiation of non-NMDA receptor transmission following fear conditioning and a depotentiation upon fear extinction, BDNF(Met/Met) mice failed to show this experience-dependent synaptic plasticity in the CEm neurons. Our results suggest that the elevated non-NMDA receptor transmission, the suppression of NMDA receptor transmission, and an impairment of synaptic plasticity in the CEm neurons might contribute to the fear extinction deficit and increased anxiety-like symptoms in BDNF Val66Met carriers.

Regulation of the mouse medial prefrontal cortical synapses by endogenous estradiol.

Recent studies suggest that low endogenous estradiol might be a susceptibility factor for anxiety and trauma-related disorders in women. Consistently, fear extinction, a form of inhibitory learning critical for the management of anxiety symptoms, is positively correlated with endogenous estradiol levels. To understand the synaptic basis of the effect of endogenous estradiol on fear extinction, we studied glutamatergic transmission and plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region crucial for the regulation of fear extinction. Diestrus mice (low estradiol) exhibited a higher basal glutamatergic transmission compared with proestrus mice (high estradiol). Synaptic plasticity was also regulated by endogenous estradiol, which favored synaptic potentiation in a GluN2B-dependent manner. Activation of estrogen receptor ß (ERß) but not ERα rescued synaptic potentiation in diestrus mice by enhancing GluN2B-mediated NMDA receptor transmission. Our results suggest that both endogenous estradiol and ERß activation facilitate the ability of the IL-mPFC synapses to undergo potentiation, a mechanism necessary for the regulation of fear extinction.