Marcelo Febo - US grants

[unreadable] DESCRIPTION (provided by applicant): Lactation provides a rewarding experience beneficial to mother-infant bonding. Cocaine addiction can sever this critical mother-infant experience, possibly affecting child psychosocial development. The main hypothesis of the proposed research is that adaptations in mesocortical dopamine function, long after chronic cocaine administration, affect maternal responsiveness to newborns. Functional MRI, in vivo microdialysis and autoradiographic methods will be employed to identify neural networks activated by suckling, a natural reward in lactating rats. Two specific aims are proposed. 1) It is hypothesized that the medial prefrontal cortex (mPFC) of cocaine sensitized dams is less responsive to suckling but will be activated by distal presentation of pups (supporting a greater appetitive drive). To test this, the neural response to distal presentation of pups or suckling stimulation is imaged in drug naive and cocaine sensitized dams. During imaging sessions, pups are housed in a special cradle that controls access to nipples or a clear plastic vivarium that simulates the maternal home cage. These data will be complemented by experiments testing for appetitive and consummately components of maternal behaviors in control and cocaine sensitized mothers. Alterations in response to suckling pups or pup cues will be accompanied by increased dopamine (DA) transporter (DAT) function with concomitant changes in extracellular DA and its receptors in the mPFC. 2) It is hypothesized that the appetitive and consummatory components of maternal responding are modulated by dopamine signaling mechanisms in the mPFC. To test this, cocaine sensitized and control mothers are given an intra-mPFC D1-, D2-like DA receptor or DAT blocker and appetitive and consummatory maternal responses analyzed. In specific aim 2, DAT binding and D1 and D2 receptor density will be assessed in brain tissue slices and mPFC DA levels measured in response to suckling pups. The studies in Specific Aim 2 will also examine DA function in the nucleus accumbens, a brain area associated, with reward seeking behavior. By understanding the neural mechanisms underlying maternal behaviors and the role of mPFC DA in the expression of these behaviors, it will be possible to target brain substrates for clinical intervention in mothers recovering from cocaine addiction. [unreadable] [unreadable] [unreadable]

ABSTRACT Apathy is diagnosed in approximately 70% of patients with dementia, including Alzheimer?s disease (AD). Changes in affective expression and reduced motivation towards daily activities is thought to involve deficits in synaptic communication between mesolimbic dopamine (DA) circuitry and hippocampus of AD patients. Our central hypothesis is that overexpression of ?-amyloid protein (A?) or hyperphosphorylated tau (p-tau) reduces neuronal activity between dorsal hippocampal CA1 (dHC-CA1), nucleus accumbens and the DA-enriched ventral tegmental area (VTA). This is predicted to be linked to reduced reward-seeking and sociability and is rescued by drugs that increase brain DA levels. The proposed research will employ high-field resting state functional magnetic resonance imaging (rsfMRI), network analysis, functional tracer-based MRI (MEMRI), and assessment of non-cognitive (affective) behaviors in A? or p-tau overexpressing mice to clarify the effects of DA drugs on reward and cognitive network activity. We will investigate the functional brain and behavioral responses to two compounds with therapeutic value for apathy and other non-cognitive affective conditions in AD, the DA reuptake inhibitor methylphenidate and the monoamine oxidase B (MAO-B) inhibitor selegiline. To test our central hypothesis, we will: (1) determine how drugs that block DA reuptake or inhibit DA breakdown affect reward-seeking and sociability in A?-expressing TgCRND8 mice and tau-expressing rTg4510 mice (aim 1), (2) investigate how these two drugs alter functional connectivity between mesolimbic and cognitive brain networks of TgCRND8 and rTg4510 mice (aim 2), and (3) determine the effect of these DAergic agents on in vivo calcium-dependent synaptic activity between the VTA and dHC-CA1 of TgCRND8 and rTg4510 mice (aim 3). We will combine cutting edge high field rsfMRI, quantification of network analysis metrics with biomarker- like properties and will apply circuit-specific contrast-based synaptic activity mapping in mice bearing human AD mutations that produce well-defined plaque or tangle pathology. From a public health perspective, the proposed studies will provide new insight on non-cognitive aspects of AD. It will contribute to clarifying the effects of A? or p-tau on functional network activity and on specific dHC-CA1 circuits, and in relation to reward/affective behaviors.