Complex social connections are essential for health and survival, and memory-impacting disorders like schizophrenia and Alzheimer’s disease can be debilitating for the relationships between patients and loved ones. To form and sustain relationships requires the ability to, first, identify strangers versus familiar individuals (identification) and, second, revise one’s representations of them based on past experience (learning). This ability is called social memory. A range of evidence confirms that the CA2 subregion of the hippocampus is crucial for social memory, and CA2-specific abnormalities are linked to social memory deficits in disease mouse models. However, the specific social cues that CA2 processes to inform social memory—as well as how CA2 adapts its responses to representations of other individuals through learning and experience—remains unclear.Since mice rely most heavily on olfaction to investigate conspecifics, odor sensory cues likely inform the basis of social identification processes in the murine brain. Furthermore, the hippocampus receives information from the olfactory bulb through the entorhinal cortex, suggesting that CA2 may be capable of processing odor sensory information for memory storage. It is already known the neighboring hippocampal subregion CA1 processes nonsocial odor cues and encodes the relationship between nonsocial odors and positive valence through learned experience. Therefore, since CA2 is necessary for social recognition overall, and since it is possible CA2 receives odor information through the same circuits as CA1, I hypothesized that CA2 processes social odor cues for social identification and combines this information with contextual information to develop and maintain social memory. In my thesis, I used two-photon calcium imaging to confirm that CA2 indeed encodes and distinguishes social odors belonging to unique individuals, as well as nonsocial odors. I also found that CA2 neurons adapt their responses to odor stimuli when a reward contingency is introduced—pairing some odors and not others with an artificial reward. Intensive decoding analyses further revealed that CA2 is capable of forming a generalized or abstract representation of social versus nonsocial and rewarded versus unrewarded social odor stimuli. Finally, with archaerhodopsin-mediated CA2 silencing, I confirmed that CA2 is necessary for social—but not nonsocial—odor-reward associative learning, further promoting the specificity of this brain region in the encoding of socially-relevant episodic memory. A link exists between CA2-specific dysfunction (namely, poor CA2 neuronal excitability) and social recognition deficits in the Df(16)A+/- microdeletion mouse model of the human 22q11.2 Deletion Syndrome—in which nearly a third of patients develop schizophrenia. I next hypothesized that CA2 in this model has a deficit in processing social sensory cues and forming the appropriate association between those cues and learned valence. Indeed, I discovered behavioral deficits in both social and nonsocial odor-reward associative learning in the Df(16)A+/- model. I further showed that CA2 is important in this impairment because selective expression of a dominant negative TREK-1 potassium channel subunit, which has been shown to improve CA2 function in these mice, rescued the deficits in social and nonsocial odor-reward learning. With two-photon imaging, I found that CA2 neurons in Df(16)A+/- mice were able to discriminate between social and nonsocial odors with an accuracy that was similar to that seen in wild-type mice, which was surprising given the CA2-dependent deficit in odor-reward learning in the Df(16)A+/- mice. However, the Df(16)A+/- mice did show a reduced fraction of neurons that were selectively activated by the rewarded odor compared to the wild-type mice. Perhaps the most salient finding is that CA2 representations in Df(16)A+/- mice showed a reduced generalized or abstract coding of odor-reward across the social and nonsocial odor categories. This suggests that the Df(16)A+/- mice failed to generalize the task variable of reward, but rather learned separate rules for social and nonsocial odor-reward association. This is reminiscent of a reduction in abstract thought in individuals with schizophrenia. Overall, my thesis provides evidence for the first time that CA2 encodes social odors and odor-reward learned experiences, that these identification and learning-related adaptation mechanisms are impaired in a disease model harboring social memory deficits, and that specific manipulations to restore CA2 function can rescue abnormal learning in this model. These results reinforce the notion that CA2 may provide a novel target for therapeutic intervention in restoring cognitive function associated with neuropsychiatric disease.

Myriad small molecule compounds targeting metabotropic glutamate receptors (mGluRs) have been investigated for the treatment of various neuropsychiatric diseases and displayed promise in preclinical studies. At the clinical level, many of these compounds have been well tolerated by human subjects but have eluded success as promising therapeutics. There are eight subtypes of mGluRs, which express as constitutive dimers. This dimerization can occur between identical (homodimerization) or different (heterodimerization) mGluR protomer subtypes, which are subject to pairing-specific signaling mechanisms. Subtype expression of mGluRs is heterogenous between brain regions and cell types, yielding probable cell-specific homo- and heterodimer combinations that respond differently to certain drugs. While G protein recruitment to active mGluR dimers has been studied extensively, little is known about arrestin recruitment to these receptors. I used bioluminescence resonance energy transfer (BRET) assays, which provide a quantitative measure of protein-protein proximity, to observe and quantify arrestin recruitment to specific mGluR subtype pairings upon ligand administration in heterologous cells. I studied how select allosteric ligands affect communication between protomers to enhance arrestin recruitment to dimers. My findings indicate that arrestin recruitment occurs only at select mGluR homodimers upon orthosteric stimulation but is frequently stimulated or enhanced by administration of activating allosteric ligands. Additionally, I found that trans-protomer communication is highly specific to mGluR protomer subtype pairings, the ligand administered,a nd inter-protomer signal direction. Lastly, my findings reveal a cooperative effect of mGluR2 and 3 heterodimerization on arrestin recruitment that is dependent on the functional ability of each protomer to bind orthosteric agonist and responds distinctively from homodimers to stimulation by certain allosteric ligands. Taken together, this work shows that mGluR signaling can be tuned using strategic pharmacology and energizes hope for future clinical success of mGluR-targeting ligands.

Thesis (M.A.)--The University of North Carolina at Greensboro, 2008. / Directed by Thomas Kwapil; submitted to the Dept. of Psychology. Title from PDF t.p. (viewed Jan. 28, 2010). Includes bibliographical references (p. ).

Thesis (Ph. D.)--University of California, San Diego, 2000. / Vita. Includes bibliographical references (leaves 148-160).

No description available.

Cognitive processes in the human brain are mediated by complex interactions among distributed brain regions. The interaction between the hippocampus and neocortical regions is crucial for physiologic and pathologic long-term episodic memory processing in the brain. However, the network mechanisms of this hippocampal-cortical communication remain unclear. To address this issue, we first designed organic materials and conformable electronics to create integrated neural interface devices that increase the spatiotemporal resolution of electrophysiologic monitoring. These devices enabled acquisition of local field potentials and action potentials of individual cortical neurons from the surface of the human brain, enhancing the ability to investigate neural network mechanisms without breaching the tissue interface. Next, we employed these devices in tandem with hippocampal probes to analyze hippocampal-cortical interactions in the context of memory tasks in freely moving rodents. We determined that in the physiologic state, the spatial properties of cortical spindle oscillations predict the likelihood of coupling with hippocampal ripples and are modulated by memory demand. In the pathologic state, we showed that interictal epileptiform discharges (IEDs), ubiquitous markers of epileptic networks, disrupt hippocampal-cortical coupling required for memory consolidation. These IEDs induce spindle oscillations in the synaptically connected cortex, producing prolonged, hypersynchronous neuronal spiking and expanding the brain territory capable of generating IEDs. Spatiotemporally targeted closed-loop electrical stimulation triggered on hippocampal IED occurrence eliminated the abnormal cortical activity patterns, preventing spread of the epileptic network and ameliorating long-term spatial memory deficits in rodents. Our findings provide new insights into mechanisms of physiologic and pathologic memory processing and offer novel approaches to therapies aimed at addressing distributed network dysfunction in neuropsychiatric disorders.

Adolescence is a sensitive developmental period encompassing neural maturation that is critical for an individual’s behavioral transition into adulthood. Due to widespread physiological changes attributed to this period, adolescents are also vulnerable to the initiation of risky behaviors, such as drug experimentation and use, as well as the emergence of various neuropsychiatric disorders. The mesocorticolimbic dopamine (DA) system in the brain undergoes a transient peak in activity and continues to mature during adolescence, potentially mediating adolescent hypersensitivity to social, appetitive, and drug-associated rewards. Simultaneously, the serotonin (5-HT) system exerts its influence on the dopamine system throughout adolescence, a process vital for proper impulse control and emotional regulation in adulthood. Substance use disorders (SUDs) are multifaceted and are comprised of diverse maladaptive behaviors that promote compulsive drug seeking, including loss of control and the propensity to engage in drug use irrespective of personal risks and/or consequences. Drug addiction and substance use have a large negative impact globally both economically and with regards to public health outcomes, representing approximately 1.3% of the global burden of disease. Furthermore, dopamine reward pathways are heavily impacted by drug use, particularly with respect to stimulants, and the level of drug-induced dopamine release in the ventral striatum can be correlated with a drug’s perceived “high.” Certain experiences and adverse behaviors linked to refinement of monoamine connectivity in the brain during adolescence, such as heightened stress and sensation seeking, may predispose individuals for developing SUDs in adulthood. However, how drug reward sensitivity and associated activity of the dopamine system is altered in adulthood as a consequence of interfering with monoamine neurodevelopment during adolescence has not been clarified. To this end, I aim to understand how imbalanced monoamine development during adolescence contributes to stimulant-mediated behaviors in adulthood, specifically contextual reward associations, in relation to in vivo activity of the dopamine reward system. I introduce a sensitive peri-adolescent (PA) period in mice, during which blockade of the serotonin transporter (SERT) via fluoxetine administration during postnatal (P) days 22-41 leads to inhibited adult aggression and locomotor response to stimulants. Conversely, I describe a more refined PA (P32-41) period during which systemic dopamine transporter (DAT) blockade via GBR12909 administration leads to enhanced aggression and stimulant-induced locomotor activity in adulthood. Utilizing these behaviorally opposing models characterized in our lab, I describe the diverging effects of systemic DAT and SERT blockade from P32-41 on cocaine-induced locomotor response as well as cocaine-mediated contextual preference. I administered cocaine intraperitoneally (i.p.) at doses of 5 and 10 mg/kg, applying the open field test and cocaine conditioned place preference (CPP) paradigm to assess stimulant-induced locomotor response and environmental reward associations, respectively. Potentiation of serotonergic tone during P32-41 via fluoxetine administration leads to decreased cocaine-induced locomotor response and a lack of preference for a cocaine-associated context in adulthood at a dose of 10 mg/kg, compared to controls and PA GBR treated subjects. Conversely, potentiation of dopaminergic tone by administering GBR12909 during P32-41 is associated with enhanced cocaine-induced locomotor reactivity at 10 mg/kg and greater contextual preference at lower doses of cocaine (5 mg/kg), in comparison to PA fluoxetine treated mice and controls. To understand how in vivo VTA dopamine population activity is altered in both PA models during cocaine-associated behaviors in adulthood, I performed cocaine CPP while recording calcium signals in VTA dopamine neurons using fiber photometry in freely behaving subjects. Importantly, I utilize these recordings as a proxy for measuring changes in VTA dopamine activity as the subjects engage with a cocaine-paired environment. I found that PA DAT blockade was associated with greater baseline VTA dopamine activity in adulthood compared to controls, as well as heightened VTA dopamine activity while the subjects were in a cocaine-paired context during selected portions of the behavioral task compared to control subjects. Additionally, we found a significant positive correlation between the magnitude of preference for a cocaine-associated context and the frequency of VTA dopamine calcium signals recorded while the subject is engaged with a cocaine-paired environment. Adult mice following PA DAT blockade displayed a greater frequency of recorded VTA dopamine calcium signals while in a cocaine-paired environment compared to PA fluoxetine treated mice. Supporting our correlational analysis, I detected a decreased preference for a cocaine-paired context in PA fluoxetine treated subjects compared to both controls and PA GBR12909 mice, when using a dose of cocaine in between the previous concentrations tested (7.5 mg/kg). Interestingly, PA fluoxetine treated subjects showed transition-dependent differences in VTA dopamine calcium activity during the final five-minute portion of our behavioral task, displaying less activity shortly post-entry into the cocaine-paired environment compared to pre-entry. In congruence, PA fluoxetine subjects showed enhanced VTA dopamine calcium activity on the saline-paired side shortly post-entry compared to pre-entry. In collaboration with the Sulzer Lab, we also probed the effects of both PA manipulations on electrically evoked dopamine release in the ventral striatum of adult anesthetized mice using fast-scan cyclic voltammetry. Electrical stimulation was targeted to the midbrain and evoked dopamine release was recorded in the ventral striatum both at baseline and in response to cocaine injection, using the same 7.5 mg/kg dose applied in the calcium imaging study. Overall, we found a significant increase in dopamine release at baseline in the ventral striatum of adult PA GBR12909 treated subjects compared to both PA fluoxetine subjects and controls. Moreover, we found significantly greater cocaine-induced dopamine release in our PA GBR12909 mice compared to controls in adulthood. These findings are consistent with the imaging and behavioral data, highlighting the persistence of an elevated dopaminergic phenotype due to systemic PA DAT blockade. Conversely, systemic PA SERT blockade leads to behaviorally opposing effects and generally lower VTA DA activity dynamics in comparison to PA GBR12909 treated subjects in adulthood. The unique, combinatorial approach applied in this dissertation work further our knowledge of how sensitive developmental periods influence the emergence of complex behaviors in adulthood, which is vital to improving treatment approaches for neuropsychiatric disorders.

No description available.

In order to assess flexibility in acquiring and using conflicting response rules, rats with selective lesions of the NBM or sham-lesion controls were subjected to serial reversal training in a simple operant discrimination paradigm. The NBM lesion group did not differ from the control group in acquisition of the original rules; the NBM lesion group required more time to master the changes in rules in the first reversal, but not in subsequent reversals.