Embedded beneath the lateral, basal and cortico-amygdaloid regions of the amygdala is the paralaminar nucleus (PL), a poorly understood structure that has evolved to be relatively larger in humans and non-human primates. Studies show that it has dense mood regulatory serotonergic connections and indicate it to be a site for amygdalar neuroplasticity (1). Corticotropin-releasing factor receptors and glucocorticoid receptors are abundantly expressed in the PL facilitating interactions between emotions, the amygdala and stress (2). As such, this amygdalar nucleus may be involved in the pathogenesis of mood disorders. Until recently, neuroimaging was unable to visualise this enigmatic nucleus in vivo. The purpose of this study was to investigate the involvement of the PL in major depressive disorder (MDD) and evaluate whether the cortisol awakening response (CAR), a measure of HPA (hypothalamic-pituitary-adrenal) axis function, was related to its volumetrics. 20 healthy human controls and 15 depressed subjects were scanned using high-resolution T1 (1mm isotropic) magnetic resonance imaging at Trinity College Institute of Neuroscience (3T, Phillips Itega). Whole amygdala and paralaminar nuclear volumes were generated using state of the art automated amygdalar segmentation in FreeSurfer 6.0 (3). Participants also provided three morning salivary cortisol samples (0, 30, 60 mins after waking). The CAR was calculating using two well-defined calculations; area under the curve with respect to ground and increase (AUCg and AUCi respectively) (4). Ethics for this study was granted under the Tallaght hospital REC. Post-hoc ANCOVAs highlighted that the left PL was smaller in patients with MDD [p = 0.018] with no change in whole amygdalar volume between groups. Partial correlations correcting for age, sex and total intracranial volume (eTIV) revealed AUGi to be inversely correlated only with the left PL in the control group [p = 0.006], whereas the AUCg was inversely correlated only with the right PL in the depressed group [p = 0.006]. A smaller left PL implicates a potential role for this amygdalar nucleus in MDD. The relationship between the left PL and the AUCi in controls is lost in the MDD group. This suggests that the smaller left PL in MDD may impact the normal cortisol response to waking, a known neuroendocrine disturbance in the disorder (5). The relationship between the AUCg and the right PL in MDD suggests that total cortisol output may be associated in right PL volumes in MDD. This is consistent with the hypothesis of cortisol oversecretion in MDD and previous findings of larger right amygdalae in MDD and right-sided amygdalar affective dominance for negative emotions. In summary, this study suggests a role for the PL in MDD and in particular a role for this nucleus at the interface between HPA stress axis dysfunction and MDD.