Biology subjects

Vaaga, C. E.

Publications and source records attributed to Vaaga, C. E..

7 recordsLinked to original sources

bioRxiv2026

Sex-specific organization and synaptic signaling in prefrontal-hypothalamic circuitry

Top down signaling from the cortex to the hypothalamus is critical to link cognitive and emotional processing to homeostasis and motivation. This study investigates signaling from the medial prefrontal cortex (mPFC) to the posterior hypothalamus (PH), a region that modulates endocrine and autonomic stress responses and motivated behaviors. The function and anatomy of this circuit was examined with patch clamp electrophysiology and mapping studies in male and female rats. Spontaneous firing properties of PH neurons were determined in a cell-type specific manner by combining a transgenic glutamic acid decarboxylase-Cre rat with Cre-dependent colorswitch virus to determine postsynaptic cell-type identity. Overall, PH neurons were more excitable in females compared to males and, in both sexes, data indicated tonic inhibition within the PH, with significantly greater inhibition in males. Using Channelrhodopsin-assisted circuit mapping to query the mPFC-PH circuit, we found that a majority of PH neurons received input from the mPFC and mPFC synapses targeted glutamatergic cells over GABAergic PH cells. Retrograde tracing revealed more PH-projecting neurons in females, specifically within the tenia tecta and infralimbic regions of the mPFC, with significantly more stress-activated PH-projecting cells in the female prelimbic cortex. Anterograde tracing revealed, surprisingly, no sex differences in mPFC presynaptic terminal density in the PH, despite more PH-projecting cell bodies in the female mPFC. These data help to elucidate the sexual divergence in cortical-hypothalamic signaling and how cognitive and emotional information from the prefrontal cortex may differentially regulate homeostasis and motivation between sexes. Significance StatementNeural signaling between the prefrontal cortex and the hypothalamus is important for maintaining homeostasis, particularly during contextual challenges such as stressors. Here we find multiple aspects of sex-specific organization and neurophysiology in this circuitry. Excitatory inputs from the medial prefrontal cortex target both excitatory and inhibitory neurons within the posterior hypothalamic nucleus in both sexes. However, there are sex differences in the number of stress-activated neurons in the prefrontal cortex that innervate the posterior hypothalamus, as well as differences in hypothalamic inhibitory signaling and estrous cycle-dependent effects on neuronal excitability. Altogether, these data suggest that organizational, synaptic, and hormonal factors may contribute to sex-specific behavioral and physiological integration.

neuroscience↗

bioRxiv2026

Optogenetic stimulation of Purkinje cells in the cerebellar vermis disrupts innate freezing behaviors and is highly aversive

The generation of adaptive defensive behaviors in response to predator threats requires the integration of sensory inputs by neural circuits to shape context-appropriate motor outputs. While the cerebellum is increasingly recognized as a contributor to non-motor behaviors, its role in regulating innate fear behaviors is only beginning to be recognized. For example, it is unclear whether and how cerebellar activity influences both the expression and experience-dependent habituation of defensive responses to ethologically relevant stimuli. Here, we examine how manipulation of cerebellar output alters innate freezing behavior and its adaptation across repeated predator-like visual stimuli. Using optogenetic stimulation of vermal Purkinje cells, we demonstrate that ongoing fastigial nucleus (FN) activity is required for the generation of appropriate freezing behaviors and further that perturbations of FN activity alter adaptive habituation across repeated trials at both short (5 minute) and long (24 hour) intervals. Our results suggest that cerebellar stimulation results in an elevated fear state, as stimulation was both anxiogenic in an open field arena and resulted in robust real-time place aversion that resisted reversal learning. Together, these findings identify the cerebellum as a key regulator of both the expression and experience-dependent adaptation of innate fear responses.

neuroscience↗

bioRxiv2025

Functional and Structural Plasticity in Cocaine-Seeking Ensembles of the Nucleus Accumbens Core

Relapse vulnerability in substance use disorder (SUD) is primarily driven by cue-induced activation of neurons within the nucleus accumbens core (NAcore), among other contributing factors. Neuronal ensembles within the NAcore, defined here as selectively co-activated neurons during specific behavioral experiences, are essential during cocaine sensitization and recall. While transient synaptic plasticity (t-SP) has been widely observed in general neuronal populations within the NAcore during reinstatement, its ensemble-specific dynamics remain unclear. Here, we used c-Fos-TRAP2-based tagging to identify cocaine-seeking ensembles in mice following cocaine intravenous self-administration, extinction, and cue-induced reinstatement. Structural spine plasticity was assessed via confocal microscopy, and functional changes were measured using whole-cell electrophysiology across multiple reinstatement time points. Ensemble neurons exhibited enhanced dendritic spine head diameter (dh) and AMPA/NMDA (A/N) ratios following cue exposure, consistent with t-SP. Notably, spine classification revealed a reduction in mature spines during reinstatement, suggesting morphological remodeling rather than new spine formation in both ensemble and non-ensemble cells. Non-ensemble neurons exhibited classical functional transient synaptic plasticity, characterized by increased A/N ratios but no significant changes in dh. To begin assessing if presynaptic vesicle release impacts t-SP, paired-pulse ratio analysis indicated no differences in population or time point. Importantly, ensemble neurons displayed elevated A/N ratio following cocaine exposure, suggesting prior silent synapse maturation. These findings demonstrate that t-SP is not uniformly distributed across NAcore neurons but differs significantly between ensemble and non-ensemble neurons. By linking ensemble identity to both structural and functional plasticity, this study refines our understanding of cue-induced relapse mechanisms. Significance StatementRelapse in substance use disorder is strongly driven by cue-induced reactivation of neuronal ensembles in the nucleus accumbens core. While transient synaptic potentiation has been widely described in bulk neuronal populations within the nucleus accumbens core, its ensemble-specific expression has remained unclear. Here, we combined c-Fos-TRAP2 tagging, confocal imaging, and slice electrophysiology to show that transient synaptic potentiation is selectively expressed in behaviorally relevant ensembles. By linking ensemble identity with structural and functional plasticity during cue-induced cocaine seeking, these findings refine current models of relapse and identify ensemble-specific plasticity as a potential target for therapeutic intervention.

neuroscience↗

bioRxiv2025

Short-term synaptic dynamics in the ventrolateral and dorsomedial periaqueductal gray

The ability to assess and rapidly respond to predator threats in the environment is necessary for survival and requires dedicated neural circuits for threat detection, sensorimotor integration, and execution of ethologically appropriate behavioral responses. Although numerous brain circuits are involved in these processes, the midbrain periaqueductal gray (PAG) serves as an important central hub to generate ethologically appropriate passive and/or active defensive behaviors. Despite its central role in generating defensive behaviors, little is known about the intrinsic and synaptic properties of neurons across columns in the PAG. To address this knowledge gap, we made whole-cell voltage- and current-clamp recordings from unlabeled neurons in the vl- and dmPAG of mice. Consistent with in vivo work, our data highlights the relative importance of synaptic inhibition in both columns. Further, our results suggest that neurons in both the vl- and dmPAG prioritize frequency-invariant coding strategies, showing remarkably stable paired pulse ratios across interstimulus intervals. Despite this common theme, the underlying mechanism each column utilizes to achieve such frequency invariant coding is distinct, reflecting important differences in synaptic processing across columns. More specifically, while the vlPAG is relatively resistant to phasic short-term depression across stimulation frequencies, neurons in the dmPAG show a pronounced buildup of tonic/slow current during high frequency stimulation trains, which counteracts short-term depression of the phasic current amplitude observed during high frequency stimulation trains. This prolonged tonic current observed in the dmPAG prolongs the period of spike elevation, suggesting that high frequency stimulation may drive sustained activity in the dmPAG. Together, these results provide fundamental information of synaptic integration and network properties across columns in the PAG, which ultimately support their distinct roles in threat processing.

neuroscience↗

bioRxiv2024

Repeated presentation of visual threats drives innate fear habituation and is modulated by environmental and physiological factors

To survive predation, animals must be able to detect and appropriately respond to predator threats in their environment. Such defensive behaviors are thought to utilize hard-wired neural circuits for threat detection, sensorimotor integration, and execution of ethologically relevant behaviors. Despite being hard-wired, defensive behaviors (i.e. fear responses) are not fixed, but rather show remarkable flexibility, suggesting that extrinsic factors such as threat history, environmental contexts, and physiological state may alter innate defensive behavioral responses. The goal of the present study was to examine how extrinsic and intrinsic factors influence innate defensive behaviors in response to visual threats. In the absence of a protective shelter, our results indicate that mice showed robust freezing behavior following both looming (proximal) and sweeping (distal) threats, with increased behavioral vigor in response to looming stimuli, which represent a higher threat imminence. Repeated presentation of looming or sweeping stimuli at short inter-trial intervals resulted in robust habituation of freezing, which was accelerated at longer inter-trial intervals, regardless of contextual cues. Finally, physiological factors such as acute stress further disrupted innate freezing habituation, resulting in a delayed habituation phenotype, consistent with a heightened fear state. Together, our results indicate that extrinsic factors such as threat history, environmental familiarity, and physiological stressors have robust and diverse effects on defensive behaviors, highlighting the behavioral flexibility in how mice respond to predator threats.

animal behavior and cognition↗

bioRxiv2017

Preferential targeting of lateral entorhinal inputs onto newly integrated granule cells

Mature dentate granule cells in the hippocampus receive input from the entorhinal cortex via the perforant path in precisely arranged lamina, with medial entorhinal axons innervating the middle molecular layer and lateral entorhinal cortex axons innervating the outer molecular layer. Although vastly outnumbered by mature granule cells, adult-generated newborn granule cells play a unique role in hippocampal function, which has largely been attributed to their enhanced excitability and plasticity (Schmidt-Hieber et al., 2004; Ge et al., 2007). Inputs from the medial and lateral entorhinal cortex carry different informational content, thus the distribution of inputs onto newly integrated granules will affect their function in the circuit. Therefore we examined the functional innervation and synaptic maturation of newly-generated dentate granule cells using retroviral labeling in combination with selective optogenetic activation of medial or lateral entorhinal inputs. Our results indicate that lateral entorhinal inputs provide nearly all the functional innervation of newly integrated granule cells. Despite preferential functional targeting, the dendritic spine density of immature granule cells was not increased in the outer molecular layer compared to the middle molecular layer. However, chronic blockade of neurotransmitter release in medial entorhinal axons with tetanus toxin disrupted normal synapse development from both medial and lateral entorhinal inputs. Our results support a role for preferential lateral perforant path input onto newly generated neurons in mediating pattern separation, but also indicates that medial perforant path input is necessary for normal synaptic development.\n\nSignificance StatementThe formation of episodic memories involves the integration of contextual and spatial information. Newly integrated neurons in the dentate gyrus of the hippocampus play a critical role in this process, despite constituting only a minor fraction of total granule cells. Here we demonstrate that these neurons preferentially receive information thought to convey the context of an experience - a unique role that each newly integrated granule cell serves for about a month before reaching maturity.

neuroscience↗

bioRxiv2017

Distinct Temporal Filters In Mitral Cells And External Tufted Cells Of The Olfactory Bulb

Short-term synaptic plasticity is a critical regulator of neural circuits, and largely determines how information is temporally processed. In the olfactory bulb, afferent olfactory receptor neurons respond to increasing concentrations of odorants with barrages of action potentials, and their terminals have an extraordinarily high release probability (Sicard, 1986; Murphy et al., 2004). These features suggest that during naturalistic stimuli, afferent input to the olfactory bulb is subject to strong synaptic depression, presumably truncating the postsynaptic response to afferent stimuli. To examine this issue, we used single glomerular stimulation in mouse olfactory bulb slices to measure the synaptic dynamics of afferent-evoked input at physiological stimulus frequencies. In cell-attached recordings, mitral cells responded to high frequency stimulation with sustained responses, whereas external tufted cells responded transiently. Consistent with previous reports (Murphy et al., 2004), olfactory nerve terminals onto both cell types had a high release probability (0.7), from a single pool of slowly recycling vesicles, indicating that the distinct responses of mitral and external tufted cells to high frequency stimulation did not originate presyaptically. Rather, distinct temporal response profiles in mitral cells and external tufted cells could be attributed to slow dendrodendritic responses in mitral cells, as blocking this slow current in mitral cells converted mitral cell responses to a transient response profile, typical of external tufted cells. Our results suggest that despite strong axodendritic synaptic depression, the balance of axodendritic and dendrodendritic circuitry in external tufted cells and mitral cells, respectively, tunes the postsynaptic responses to high frequency, naturalistic stimulation.\n\nKey PointsO_LIThe release probability of the ORN is reportedly one of the highest in the brain (Murphy et al., 2004), which is predicted to impose a transient temporal filter on postsynaptic cells.\nC_LIO_LIMitral cells responded to high frequency ORN stimulation with sustained transmission, whereas external tufted cells responded transiently.\nC_LIO_LIThe release probability of ORNs (0.7) was equivalent across mitral and external tufted cells and could be explained by a single pool of slowly recycling vesicles.\nC_LIO_LIThe sustained response in mitral cells resulted from dendrodendritic amplification in mitral cells, which was blocked by NMDA and mGluR1 receptor antagonists, converting mitral cell responses to transient response profiles.\nC_LIO_LIOur results suggest that although the afferent ORN synapse shows strong synaptic depression, dendrodendritic circuitry in mitral cells produces robust amplification of brief afferent input, thus the relative strength of axodendritic and dendrodendritic input determines the postsynaptic response profile.\nC_LI

neuroscience↗