Stepping up to COVID-19: A Clinical Trial of a Telepsychology Positive Parenting Program Targeting Behavior Problems in Children With Neurological Risk.

OBJECTIVE: To evaluate the feasibility, acceptability, and preliminary efficacy of a stepped-care parenting program implemented during COVID-19 among families of behaviorally at-risk children with neurological or neurodevelopmental disorders aged 3-9 years. METHODS: Stepped-care I-InTERACT-North increased psychological support across 3 steps, matched to family needs: (1) guided self-help (podcast), (2) brief support, and (3) longer-term parent support. The intervention was provided by clinicians at The Hospital for Sick Children. Recruitment occurred via hospital and research cohort referral. A single-arm trial using a pragmatic prospective pre-post mixed-method design was utilized to assess accrual, engagement, acceptability, and preliminary efficacy. RESULTS: Over 15 months, 68 families enrolled (83% consent rate) and 56 families completed stepped-care (Step 1 = 56; Step 2 = 39; Step 3 = 28), with high adherence across Steps (100%, 98%, and 93%, respectively). Parents reported high acceptability, reflected in themes surrounding accessibility, comprehension, effectiveness, and targeted care. Positive parenting skill increases were documented, and robust improvement in child behavior problems was apparent upon Step 3 completion (p =.001, d = .390). Stepped-care was as effective as traditional delivery, while improving consent and completion rates within a pandemic context. CONCLUSIONS: This stepped-care telepsychology parenting program provides a compelling intervention model to address significant gaps in accessible mental health intervention while simultaneously balancing the need for efficient service. Findings inform program scalability beyond COVID-19 and emphasize the value of stepped-care intervention in delivering and monitoring mental health treatment.

Similar nicotinic excitability responses across the developing hippocampal formation are regulated by small-conductance calcium-activated potassium channels.

The hippocampal formation forms a cognitive circuit that is critical for learning and memory. Cholinergic input to nicotinic acetylcholine receptors plays an important role in the normal development of principal neurons within the hippocampal formation. However, the ability of nicotinic receptors to stimulate principal neurons across all regions of the developing hippocampal formation has not been determined. We show in this study that heteromeric nicotinic receptors mediate direct inward current and depolarization responses in principal neurons across the hippocampal formation of the young postnatal mouse. These responses were found in principal neurons of the CA1, CA3, dentate gyrus, subiculum, and entorhinal cortex layer VI, and they varied in magnitude across regions with the greatest responses occurring in the subiculum and entorhinal cortex. Despite this regional variation in the magnitude of passive responses, heteromeric nicotinic receptor stimulation increased the excitability of active principal neurons by a similar amount in all regions. Pharmacological experiments found this similar excitability response to be regulated by small-conductance calcium-activated potassium (SK) channels, which exhibited regional differences in their influence on neuron activity that offset the observed regional differences in passive nicotinic responses. These findings demonstrate that SK channels play a role to coordinate the magnitude of heteromeric nicotinic excitability responses across the hippocampal formation at a time when nicotinic signaling drives the development of this cognitive brain region. This coordinated input may contribute to the normal development, synchrony, and maturation of the hippocampal formation learning and memory network. NEW & NOTEWORTHY This study demonstrates that small-conductance calcium-activated potassium channels regulate similar-magnitude excitability responses to heteromeric nicotinic acetylcholine receptor stimulation in active principal neurons across multiple regions of the developing mouse hippocampal formation. Given the importance of nicotinic neurotransmission for the development of principal neurons within the hippocampal formation, this coordinated excitability response is positioned to influence the normal development, synchrony, and maturation of the hippocampal formation learning and memory network.

A Novel Multisensory Integration Task Reveals Robust Deficits in Rodent Models of Schizophrenia: Converging Evidence for Remediation via Nicotinic Receptor Stimulation of Inhibitory Transmission in the Prefrontal Cortex.

Atypical multisensory integration is an understudied cognitive symptom in schizophrenia. Procedures to evaluate multisensory integration in rodent models are lacking. We developed a novel multisensory object oddity (MSO) task to assess multisensory integration in ketamine-treated rats, a well established model of schizophrenia. Ketamine-treated rats displayed a selective MSO task impairment with tactile-visual and olfactory-visual sensory combinations, whereas basic unisensory perception was unaffected. Orbitofrontal cortex (OFC) administration of nicotine or ABT-418, an α4ß2 nicotinic acetylcholine receptor (nAChR) agonist, normalized MSO task performance in ketamine-treated rats and this effect was blocked by GABAA receptor antagonism. GABAergic currents were also decreased in OFC of ketamine-treated rats and were normalized by activation of α4ß2 nAChRs. Furthermore, parvalbumin (PV) immunoreactivity was decreased in the OFC of ketamine-treated rats. Accordingly, silencing of PV interneurons in OFC of PV-Cre mice using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) selectively impaired MSO task performance and this was reversed by ABT-418. Likewise, clozapine-N-oxide-induced inhibition of PV interneurons in brain slices was reversed by activation of α4ß2 nAChRs. These findings strongly imply a role for prefrontal GABAergic transmission in the integration of multisensory object features, a cognitive process with relevance to schizophrenia. Accordingly, nAChR agonism, which improves various facets of cognition in schizophrenia, reversed the severe MSO task impairment in this study and appears to do so via a GABAergic mechanism. Interactions between GABAergic and nAChR receptor systems warrant further investigation for potential therapeutic applications. The novel behavioral procedure introduced in the current study is acutely sensitive to schizophrenia-relevant cognitive impairment and should prove highly valuable for such research. SIGNIFICANCE STATEMENT: Adaptive behaviors are driven by integration of information from different sensory modalities. Multisensory integration is disrupted in patients with schizophrenia, but little is known about the neural basis of this cognitive symptom. Development and validation of multisensory integration tasks for animal models is essential given the strong link between functional outcome and cognitive impairment in schizophrenia. We present a novel multisensory object oddity procedure that detects selective multisensory integration deficits in a rat model of schizophrenia using various combinations of sensory modalities. Moreover, converging data are consistent with a nicotinic-GABAergic mechanism of multisensory integration in the prefrontal cortex, results with strong clinical relevance to the study of cognitive impairment and treatment in schizophrenia.

Postsynaptic nicotinic acetylcholine receptors facilitate excitation of developing CA1 pyramidal neurons.

The hippocampus plays a key role in learning and memory. The normal development and mature function of hippocampal networks supporting these cognitive functions depends on afferent cholinergic neurotransmission mediated by nicotinic acetylcholine receptors. Whereas it is well-established that nicotinic receptors are present on GABAergic interneurons and on glutamatergic presynaptic terminals within the hippocampus, the ability of these receptors to mediate postsynaptic signaling in pyramidal neurons is not well understood. We use whole cell electrophysiology to show that heteromeric nicotinic receptors mediate direct inward currents, depolarization from rest and enhanced excitability in hippocampus CA1 pyramidal neurons of male mice. Measurements made throughout postnatal development provide a thorough developmental profile for these heteromeric nicotinic responses, which are greatest during the first 2 wk of postnatal life and decrease to low adult levels shortly thereafter. Pharmacological experiments show that responses are blocked by a competitive antagonist of α4ß2* nicotinic receptors and augmented by a positive allosteric modulator of α5 subunit-containing receptors, which is consistent with expression studies suggesting the presence of α4ß2 and α4ß2α5 nicotinic receptors within the developing CA1 pyramidal cell layer. These findings demonstrate that functional heteromeric nicotinic receptors are present on CA1 pyramidal neurons during a period of major hippocampal development, placing these receptors in a prime position to play an important role in the establishment of hippocampal cognitive networks.

Sex differences in the nicotinic excitation of principal neurons within the developing hippocampal formation.

The hippocampal formation (HF) plays an important role to facilitate higher order cognitive functions. Cholinergic activation of heteromeric nicotinic acetylcholine receptors (nAChRs) within the HF is critical for the normal development of principal neurons within this brain region. However, previous research investigating the expression and function of heteromeric nAChRs in principal neurons of the HF is limited to males or does not differentiate between the sexes. We used whole-cell electrophysiology to show that principal neurons in the CA1 region of the female mouse HF are excited by heteromeric nAChRs throughout postnatal development, with the greatest response occurring during the first two weeks of postnatal life. Excitability responses to heteromeric nAChR stimulation were also found in principal neurons in the CA3, dentate gyrus, subiculum, and entorhinal cortex layer VI (ECVI) of young postnatal female HF. A direct comparison between male and female mice found that principal neurons in ECVI display greater heteromeric nicotinic passive and active excitability responses in females. This sex difference is likely influenced by the generally more excitable nature of ECVI neurons from female mice, which display a higher resting membrane potential, greater input resistance, and smaller afterhyperpolarization potential of medium duration (mAHP). These findings demonstrate that heteromeric nicotinic excitation of ECVI neurons differs between male and female mice during a period of major circuitry development within the HF, which may have mechanistic implications for known sex differences in the development and function of this cognitive brain region.

Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid ß in SH-SY5Y cells and primary cortical neurons.

Gonadal steroid hormones exert neurotrophic and neuroprotective effects on the brain. Recent work suggests potential neuroprotective roles for the 3α-hydroxy, 5α-reduced metabolites of these hormones. Two such metabolites are 5α-androstane-3α,17ß-diol (3α-diol) and 5α-pregnan-3α-ol-20-one (allopregnanolone; Allo), which may contribute to the overall protection conferred by their precursors (testosterone and progesterone, respectively) through mechanisms including potentiation of gamma-aminobutyric acid (GABA)A receptor (GABAAR) activity. We have previously demonstrated that physiological concentrations of 3α-diol inhibit prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and the associated neurotoxicity resulting from amyloid ß peptide 1-42 (Aß42) exposure in vitro. In the present study, we sought to characterize the GABAAR-dependency of 3α-diol's effects, compared to those of Allo, in SH-SY5Y human female neuroblastoma cells and primary cortical neurons isolated from postnatal day 0-1 mice. Both 3α-diol and Allo prevented Aß42-mediated ERK phosphorylation in SH-SY5Y cells, with substantially different concentration requirements (10 nM for 3α-diol, 100 nM for Allo). Pharmacological inhibition of GABAAR with picrotoxin did not prevent this effect, indicating that neurosteroid-mediated ERK inhibition in SH-SY5Y cells may be GABAAR-independent. While 10 nM and 100 nM concentrations of both neurosteroids inhibited ERK phosphorylation induced by Aß42 in primary cortical neurons, which have high expression levels of GABAARs, only the effects of Allo were significantly inhibited by picrotoxin. These results suggest that neurosteroid metabolites of testosterone and progesterone may contribute to neuroprotection by suppressing ERK phosphorylation through both GABAAR-dependent and -independent mechanisms.